Signature of cycling hypoxia and use thereof for the prognosis of cancer

ABSTRACT

The present invention relates to a signature comprising at least 2 cycling hypoxia markers. The present invention also relates to a non-invasive method for the prognosis of cancer in a subject, wherein said method comprises assessing the expression of markers of a signature of the invention in a sample from said subject; and to a kit for implementing this non-invasive method.

FIELD OF INVENTION

The present invention relates to the field of cancer prognosis. More specifically, the present invention relates to a signature based on differential gene expression in conditions of cycling hypoxia, for the prognosis of cancer in a subject.

BACKGROUND OF INVENTION

Cancer is a general term referring to a broad group of diseases characterized by unregulated and uncontrolled cell growth and division. These diseases caused in 2007 about 8 million death worldwide, and are currently the second leading cause of death in developed countries. As prognostic and response to treatments are subject-dependent, there is a need for prognostic and/or predictive means, allowing estimating for each subject the progression of his/her disease and/or his/her response to a given treatment.

Several prognostic or predictive means are currently known in the prior art. Among them, some correspond to a signature, i.e. are based on specific gene expression of tumors or peritumoral tissues.

For example, the European patent application EP 1 754 795 describes a method for predicting relapse of breast cancer in bone by analyzing the expression of a group of 76 genes. This prognostic signature is known in the art as the Gene76 signature.

Moreover, the international patent application WO 02/103320 describes genetic markers whose expression is correlated with breast cancer. More specifically, this patent application describes a genetic signature comprising 70 genes, known as Gene70 or Mammaprint, for the diagnosis and the prognosis of breast cancer in a subject.

Furthermore, the international patent application WO2006/052862 describes a signature useful for predicting whether cancer patients are likely to have a beneficial response to treatment with chemotherapy. The specific signature disclosed by WO2006/052862 corresponds to the Oncotype DX signature developed for breast cancer patients.

Both Oncotype DX signature and Mammaprint signature are approved for clinical use.

However, the signatures of the prior art present the drawback to be designed for one type of cancer only. For example, the above cited signatures were developed for breast cancer. There is thus a need for a genetic signature that may be used for the prognosis of not only one cancer type, but of several cancers. Especially, there is a need for a signature that may be used for the prognosis of all tumors.

A common characteristic of tumors is cycling hypoxia. Cycling hypoxia corresponds to a temporal instability in oxygen transport, as a result of instabilities in microvessel red blood cell flux within tumors. Indeed, tumor angiogenesis and glycolytic metabolism are two responses of cancer cells to a deficit in oxygen. The building of new blood vessels to bring O₂ and the uncoupling from mitochondrial oxidative phosphorylation to survive under low O₂ are actually two complementary responses to hypoxia. These somehow opposite modes of adaptation account for local and temporal heterogeneities in tumor O₂ distribution. The extent of cycling hypoxia may reflect tumor plasticity and thus may be a mark of the capacity of tumor cells to survive and proliferate in a hostile environment.

The inventors herein showed that cycling hypoxia has the potential to lead to common alterations in the expression of some transcripts. They thus developed a signature of cycling hypoxia of particular clinical relevance for the prognosis of cancers.

SUMMARY

The present invention thus relates to a signature comprising at least 2 cycling hypoxia markers. In one embodiment, the signature comprises at least 3, preferably at least 5, more preferably at least 10 cycling hypoxia markers. In one embodiment, said cycling hypoxia markers are selected from the list of 1379 cycling hypoxia markers of Table 1, fragments, variants and equivalents thereof. In another embodiment, said cycling hypoxia markers are selected from the list of 651 cycling hypoxia markers of Table 2, fragments, variants and equivalents thereof. In another embodiment, said cycling hypoxia markers are selected from the list of 298 cycling hypoxia markers of Table 3, fragments, variants and equivalents thereof. In another embodiment, said cycling hypoxia markers are selected from the list of 167 cycling hypoxia markers of Table 4, fragments, variants and equivalents thereof. In another embodiment, said cycling hypoxia markers are selected from the list of 96 cycling hypoxia markers of Table 5, fragments, variants and equivalents thereof. In another embodiment, said cycling hypoxia markers are selected from the list of 74 cycling hypoxia markers of Table 6, fragments, variants and equivalents thereof. In another embodiment, said cycling hypoxia markers are selected from the list of 37 cycling hypoxia markers of Table 7, fragments, variants and equivalents thereof. In another embodiment, said cycling hypoxia markers are selected from the list of 10 cycling hypoxia markers of Table 8, fragments, variants and equivalents thereof. In another embodiment, said signature comprises the 10 cycling hypoxia markers of Table 8, variants, fragments and equivalents thereof.

The present invention also relates to a non-invasive method for the prognosis of cancer in a subject, or for predicting the response of a subject to a specific treatment, wherein said method comprises assessing the expression of markers of a signature as described hereinabove in a sample from said subject. Therefore, the present invention also relates to a non-invasive method for the prognosis of cancer in a subject, or for predicting the response of a subject to a specific treatment, wherein said method comprises assessing the expression of markers of a signature comprising at least 2 cycling hypoxia markers in a sample from said subject. In one embodiment, the signature comprises at least 3, preferably at least 5, more preferably at least 10 cycling hypoxia markers. In one embodiment, the cycling hypoxia markers are selected from the list of 1379 cycling hypoxia markers of Table 1, fragments, variants and equivalents thereof. In one embodiment, the cycling hypoxia markers are selected from the list of 651 cycling hypoxia markers of Table 2, fragments, variants and equivalents thereof. In one embodiment, the cycling hypoxia markers are selected from the list of 298 cycling hypoxia markers of Table 3, fragments, variants and equivalents thereof. In one embodiment, the cycling hypoxia markers are selected from the list of 167 cycling hypoxia markers of Table 4, fragments, variants and equivalents thereof. In one embodiment, the cycling hypoxia markers are selected from the list of 96 cycling hypoxia markers of Table 5, fragments, variants and equivalents thereof. In one embodiment, the cycling hypoxia markers are selected from the list of 74 cycling hypoxia markers of Table 6, fragments, variants and equivalents thereof. In one embodiment, the cycling hypoxia markers are selected from the list of 37 cycling hypoxia markers of Table 7, fragments, variants and equivalents thereof. In one embodiment, the cycling hypoxia markers are selected from the list of 10 cycling hypoxia markers of Table 8, fragments, variants and equivalents thereof. In one embodiment, the signature comprises the 10 cycling hypoxia markers of Table 8, variants, fragments and equivalents thereof.

In one embodiment, said method comprises mathematically combining the expression profile of markers in a score. In one embodiment, said sample is a biopsy sample or a bodily fluid sample of said subject. In one embodiment, the method of the invention further comprises comparing said expression with a reference expression profile.

The present invention further relates to a kit for determining the expression profile of a genetic signature as described hereinabove, or for implementing the non-invasive method as described hereinabove, wherein said kit comprises means for determining the expression of the cycling hypoxia markers of the signature of the invention. In one embodiment, said means for determining the expression of the markers of the signature is a microarray comprising probes specific for said cycling hypoxia markers. In another embodiment, said means for determining the expression of the cycling hypoxia markers are qPCR primers specific for said cycling hypoxia markers.

DEFINITIONS

In the present invention, the following terms have the following meanings:

-   -   “Prognosis” refers to the likelihood of cancer-attributable         death or cancer progression, including recurrence and metastatic         spread of a neoplastic disease, during the natural history of         the disease, or to the likelihood of a beneficial response to a         specific treatment, wherein a beneficial response means an         improvement in any measure of patient status including, but not         limited to, overall survival, long-term survival (i.e. survival         for at least 3, preferably at least 5, 8, or 10 years following         diagnosis, surgery or other treatment), recurrence-free         survival, and distant recurrence-free survival. Accordingly, a         “prognostic signature” refers to a signature that may be used         for the prognosis of a subject. In one embodiment, the term         “prognostic signature” also includes “predictive signature”,         wherein said term refers to a signature that may be used for         anticipating the response of a subject to a specific treatment.     -   “Normoxia” refers to an oxygen tension condition corresponding         to healthy tissues. In one embodiment, in conditions of in vitro         cell culture, normoxia may refer to a condition with a         concentration of O₂ ranging from about 10 to about 21%,         preferably from about 15 to about 21%, and more preferably of         about 20-21% O₂.     -   “Hypoxia” refers to a condition wherein the oxygen tension is         inferior to the oxygen tension of healthy tissues. In one         embodiment, in conditions of in vitro cell culture, hypoxia may         refer to a condition with at most 5% O₂, preferably to a         condition with about 1% O₂.     -   “Cycling hypoxia” (also known as “cyclic hypoxia”) refers to a         temporal instability in oxygen transport. Cycling hypoxia thus         corresponds to alternating normoxia and hypoxia cycles.     -   “Signature” refers to a group of markers (i.e. at least 2,         preferably at least 3, more preferably at least 5, and even more         preferably at least 10 markers) whose combined expression         profile is indicative of a biological condition (such as, for         example, cycling hypoxia), or of a particular prognosis or of a         particular response of a subject to a treatment.     -   A “marker” corresponds to a nucleotide sequence isolated from         the genome, preferably to a gene in the genome, i.e. each marker         is identifiable as all or a portion of a gene. A marker may thus         correspond to an entire gene, or to an EST (wherein EST stands         for Expressed Sequence Tag) derived from this gene.     -   “Expression” refers interchangeably to expression of a marker,         including the encoded polypeptide or protein. Expression of a         marker may be determined, for example, by immunoassay using one         or more antibody(ies) that bind(s) with the polypeptide.         Alternatively, expression of a marker may be determined by         measurement of mRNA levels, for example, by RT-PCR, RT-qPCR         (wherein qPCR stands for quantitative PCR), or using a         microarray, or using sequencing methods. In one embodiment, the         term “expression” of a marker may also refer to modification of         a protein or peptide, preferably to post-translational         modification of a protein or peptide.     -   “Subject” refers to an animal, preferably a mammal, more         preferably a human. In one embodiment, the subject is a patient,         i.e. a recipient of health care services. Preferably, the         subject is a cancer patient, i.e. he/she was previously         diagnosed with cancer.     -   “About” preceding a figure means plus or less 10% of the value         of said figure.

DETAILED DESCRIPTION

The present invention first relates to a signature of cycling hypoxia, wherein said signature comprises markers whose expression is different between a normoxic condition and a cycling hypoxia condition.

In one embodiment of the invention, the signature of the invention comprises at least 2 markers, preferably at least 3 markers, 4 markers, more preferably at least 5 markers, and even more preferably at least 10 markers.

The present invention thus also relates to a marker whose expression is different between a normoxic condition and a cycling hypoxia condition. A marker whose expression is different between a normoxic condition and a cycling hypoxia condition will be hereinafter referred as a “cycling hypoxia marker”.

Methods for determining cycling hypoxia markers are well-known from the skilled artisan, and include, without limitation, comparing the transcriptome (in an embodiment wherein expression relates to transcription of a marker) or proteome (in an embodiment wherein expression relates to translation of a marker) in a condition of normoxia and in a condition of cycling hypoxia. An example of such a method, based on the comparison of transcriptomes, is presented in the Examples.

Examples of post-translational modifications of a protein or peptide include, but are not limited to, phosphorylation, myristoylation, palmitoylation, isoprenylation, glypiation, lipoylation, O-, N- or S-acylation, alkylation, glycosylation, malonylation, hydroxylation, nucleotide addition, oxidation, sumoylation, ubiquitination, citrullination, deamidation, formation of disulfide bridges, proteolytic cleavage, racemization and the like. Examples of methods for assessing post-translational modifications of a protein or peptide include, but are not limited to, mass spectroscopy, immunoblotting, Eastern blotting, and the like.

In one embodiment of the invention, a marker is considered as differentially expressed in conditions of normoxia and cycling hypoxia if, according to a t-test, the p-value after FDR correction is lower than 0.05, preferably lower than 0.01.

In one embodiment, cycling hypoxia markers are selected from the list of the 1379 cycling hypoxia markers of Table 1 below, as well as their variants, fragments or equivalents. Table 1 comprises cycling hypoxia markers identified in the conditions of the Example and presenting a p-value after FDR correction lower than 0.05.

Pathways refer to the KEGG pathway database (http://www.genome.jp/kegg/).

In the Table 1 below, and in Tables 2-8, probesets are indicated according to the nomenclature of “Human gene 1.0ST”.

TABLE 1 GeneBank Name of the Accession Number marker Pathways Probeset NR_002312 RPPH1 7977507 BC018448 MALAT1 7949410 NR_003287 RN28S1 7942875, 8059576, 7917645, 7942791 or 8151234 AF284753 UIMC1 7911343 or 8165703 NM_014248 RBX1 03420, 04110, 8073334 04114, 04120, 04141, 04310, 04350, 04710, 05200, 05211 NM_177987 TUBB8 04145, 04540, 7911355 05130 NM_170601 SIAE 7944867 NM_001012708 KRTAP5-3 7945652 NR_029710 MIR193A 8006321 NM_000981 RPL19 3010 8006845 NM_012217 TPSD1 7992191 NM_003792 EDF1 8165309 BC013044 DNAJA2 4141 7995379 NR_029824 MIR128-2 8078527 NM_004352 CBLN1 8001329 NM_001017 RPS13 3010 7946812 NM_001037160 CYS1 8050232 NM_003731 SSNA1 8159609 NM_006160 NEUROD2 8014865 NM_001417 EIF4B 03013, 04150 7963575 NM_017854 TMEM160 8037853 NM_016057 COPZ1 7955896 NM_152568 NKX6-3 8150433 NM_016170 TLX2 8042896 NR_002715 RN7SL1 8040338 NM_016564 CEND1 7945536 AK302042 LOC440518 8027343 NM_014206 C11orf10 7948606 NR_033335 SNORA70G 7964830 NM_003094 SNRPE 3040 8160033 or 7908988 NM_012322 LSM5 03018, 03040 8138912 NM_145232 CTU1 4122 8038782 NR_029583 MIR197 7903717 NM_032231 FAM96A 7989611 NR_024583 POM121L8P 8071168 NM_007241 SNF8 4144 8016508 NM_000307 POU3F4 8168567 NM_013299 SAC3D1 7941122 NM_005608 PTPRCAP 7949792 NM_006327 TIMM23 7927548 NM_016424 LUC7L3 8016733 NM_144615 TMIGD2 8032782 NM_001135086 PRSS41 7992716 NM_003512 HIST1H2AC 5322 8117372 NM_000863 HTR1B 4080 8127692 NM_145203 CSNK1A1L 04310, 04340 7971071 NR_000009 SNORD4B 8005957 NM_001080113 C14orf184 7980859 AK123383 LOC642648 8076747 NM_032479 MRPL36 8110861 or 8180305 NM_031210 SLIRP 7975989 NM_023002 HAPLN4 8035646 NM_182532 TMEM61 7901687 NM_003538 HIST1H4A 5322 8117334 AK125166 LOC441268 8141166 NM_001001521 UGP2 00040, 00052, 8052624 00500, 00520, 01100 NR_001445 RN7SK 8120249 NM_001551 IGBP1 8168087 NM_138417 KTI12 7916130 NM_031213 FAM108A1 8032371, 7904869, 7904948, 7924230 or 8074842 BC001181 FAM173A 7992043 NM_001031 RPS28 3010 8005471, 8025395 or 7942824 NM_004175 SNRPD3 03040, 05322 8071920 NM_001044370 MPPED1 8073623 BC005079 C2orf42 8052834 NM_003542 HIST1H4C 5322 8117368 BC033986 LOC440934 8048712 NM_001082575 RBFOX3 8018993 NM_017900 AURKAIP1 7911532 or 8039923 NM_001024598 HES3 7897280 NM_022061 MRPL17 7946267 NM_001029 RPS26 3010 8007797 or 8154363 NM_016060 MED31 8011968 NM_012394 PFDN2 7921786 NM_015965 NDUFA13 00190, 05010, 8027205 05012, 05016 NM_080603 ZSWIM1 8063074 NM_021104 RPL41 3010 7957530, 7965467, 7982129, 8105432, 8075691 or 8061364 NM_000847 GSTA3 00480, 00980, 8127087 00982 NM_032753 RAX2 8032601 NM_003684 MKNK1 04010, 04910 7915846 NM_003577 UTF1 7931553 NM_022363 LHX5 7966631 NM_001037495 DYNLL1 4962 7967067 or 7959164 NM_004609 TCF15 8064370 AK098732 TRAP1 7992954 NM_144999 LRRC45 8010719 NM_001018138 NME2 00230, 00240, 8180388, 01100 8180389, 8180387 or 8180386 NM_002528 NTHL1 3410 7998692 NM_006087 TUBB4 04145, 04540, 8025051 05130 NM_003493 HIST3H3 5322 7924884 NR_026800 KIAA0125 7977440 NM_015456 COBRA1 8159654 NM_006088 TUBB2C 04145, 04540, 8165496 05130 NM_002307 LGALS7 8036584 or 8028546 NM_181887 UBE2D3 04120, 04141 8180330, 8180335, 8180334, 8180331, 8180333, 8180329, 8180332 or 8102024 NM_001348 DAPK3 05200, 05219 8032718 NM_005319 HIST1H1C 8124397 NM_178536 LCN12 8159501 NR_003666 SPDYE7P 8133209 AK125308 LOC100129484 8137962 NM_020412 CHMP1B 4144 8020179 NM_003550 MAD1L1 04110, 04914 8137805 NM_032527 ZGPAT 8064156 NR_003051 RMRP 8161024 NR_029681 MIR140 7997008 NM_006858 TMED1 8034101 NM_006312 NCOR2 4330 7959772 AK095987 FLJ38668 8054449 ENST00000427835 C20orf61 8065013 NM_001144936 C11orf95 7949015 NM_173547 TRIM65 8018502 NM_014370 SRPK3 8170753 NM_005574 LMO2 7947450 NM_001007595 C2CD4B 7989473 NM_001168 BIRC5 05200, 05210 8018860 NM_021012 KCNJ12 8005726 NM_144589 COMTD1 7934544 NM_016589 TIMMDC1 8081867 NM_012315 KLK9 8038716 NM_006292 TSG101 4144 7947015 NM_033055 HIAT1 7903294 NM_001113201 NACA 7964262 NM_181838 UBE2D2 04120, 04141, 8108435 05131 NM_005973 PRCC 7906235 NM_005274 GNG5 4062 8174509 NM_006770 MARCO 4145 8044773 NM_014674 EDEM1 4141 8085116 NM_145657 GSX1 7968260 NM_002003 FCN1 8165011 NM_003001 SDHC 00020, 00190, 8011212 01100, 05010, 05012, 05016 NM_018942 HMX1 8104136 NM_006848 CCDC85B 7941457 NM_032338 LLPH 7956876 NM_015971 MRPS7 8009784 NM_020180 CELF4 8022952 NM_001080495 TNRC18 8137959 NM_006181 NTN3 4360 7992632 AK094921 LOC100131763 8049950 NM_198545 C1orf187 7897737 NM_002066 GML 8148565 NM_031899 GORASP1 8086317 NM_012452 TNFRSF13B 04060, 04672, 8013061 05340 NM_138574 HDGFL1 8117172 NM_024816 RABEP2 8000616 NM_022097 CHP2 04010, 04020, 7994123 04114, 04210, 04310, 04360, 04370, 04650, 04660, 04662, 04720, 05010, 05014 NM_006801 KDELR1 5110 8038078 NM_004939 DDX1 8040386 NM_130784 SYCE1 7937247 NM_019082 DDX56 8139392 NM_001039916 ZNF384 7953390 NM_016602 CCR10 04060, 04062, 8015681 04672 NR_024591 POM121L1P 8074714 or 8074867 NM_020064 BARHL1 8158912 NM_006356 ATP5H 00190, 01100, 8018288 05010, 05012, 05016 NM_012249 RHOQ 4910 8041808 NR_002951 SNORA2B 7962829 NR_004430 RNU1-1 7919269, 7919349, 7898375, 7898411, 7912800, 7912850, 7919576, 7973896 or 7978568 NM_001126128 PROK2 8088813 NM_016063 HDDC2 8129363 NM_005706 TSSC4 7937813 NR_002781 TSPY26P 8065603 NM_175064 SPDYE1 8140424, 8140454 or 8132531 NM_138350 THAP3 7897329 AY730278 CENPVL1 8167652 or 8172715 NM_002669 PLRG1 3040 8103289 NM_006476 ATP5L 00190, 01100 7944216 NM_031909 C1QTNF4 7947928 NM_032805 ZSCAN10 7998921 NM_001804 CDX1 8109226 NM_014976 PDCD11 7936096 AK097604 LOC100130285 7998265 NM_003168 SUPT4H1 8016982 NM_016835 MAPT 04010, 05010 8016263 NM_001002 RPLP0 3010 8109750 or 7966996 NM_016305 SS18L2 8079074 NM_001033113 ENTPD8 00230, 00240 8165538 NM_003926 MBD3 8032275 NM_031280 MRPS15 7914940 NR_026676 RPS2P32 8131869 NM_145803 TRAF6 04010, 04120, 7947540 04144, 04380, 04620, 04621, 04622, 04722, 05140, 05142, 05145, 05160, 05200, 05222, NM_000858 GUK1 00230, 01100 7910241 NM_139172 TMEM190 8031475 NM_018047 RBM22 3040 8115168 NM_182702 PRSS42 8086683 NM_003859 DPM1 00510, 01100 8067017 NM_003002 SDHD 00020, 00190, 7943853 or 01100, 05010, 7899016 05012, 05016, NR_026716 KIR3DX1 8031200 NM_015719 COL5A3 04510, 04512, 8033825 04974, 05146 L20860 SEPT5-GP1BB 8071272 NM_101395 DYRK1A 8068551 NM_014419 DKKL1 8030292 NR_026557 PLK5 8024331 BC043386 C19orf68 8029996 NM_001080440 OTOL1 8083770 NM_144578 MAPK1IP1L 7974455 NM_012145 DTYMK 00240, 01100 8060286 or 8077262 NM_002804 PSMC3 3050 7947867 NM_001172743 RAI2 8171539 NM_016547 SDF4 7911422 NM_175741 C15orf55 7982516 NM_003910 BUD31 3040 8134589 NM_014342 MTCH2 7947934 NM_001013 RPS9 3010 8180398 or 8031152 NM_021646 ZNF500 7999196 AY341951 FAM138D 7960172 NM_005034 POLR2K 00230, 00240, 8147654 01100, 03020, 05016 NM_001005922 KRTAP5-1 7945645 NM_001105669 TTC24 7906177 NM_006043 HS3ST2  534 7994052 NM_173641 EPHA10 7915078 NM_001010908 C1QL3 7932308 NM_001164094 COPS7A 7953395 NM_014582 OBP2A 8180231 NM_024319 C1orf35 7924842 NM_003375 VDAC2 04020, 05012, 8042335 or 05016 7928524 NM_007374 SIX6 7974793 NM_001003684 UQCR10 00190, 01100, 8072274 04260, 05010, 05012, 05016 NR_000025 SNORD15B 7942594 AF304442 C21orf118 8068046 NM_016312 WBP11 3040 7961489 NM_080875 MIB2 7896985 NM_005922 MAP3K4 04010, 04912 8130624 NR_002576 SNORA21 8014755 NM_018462 BRK1 4810 8085287 NR_003013 SCARNA16 8010137 NM_005609 PYGM 00500, 04910 7949124 NM_016438 HIGD1B 8007701 NM_004855 PIGB 00563, 01100 7983811 NR_026713 FAM182A 8065527 or 8061490 NM_003537 HIST1H3B 5322 8124388 NM_001040436 YARS2  970 7962203 NM_014171 CRIPT 8041813 NM_053056 CCND1 04110, 04115, 7950012 04310, 04510, 04630, 05200, 05210, 05212, 05213, 05214, 05215, 05216, 05218, 05219, 05220, 05221, 05222, 05223, 05416 AF067420 IGHA1 7995263 or 7981722 NM_198180 QRFP 8164630 BC004224 SHANK2-AS3 7942228 NM_019107 C19orf10 8032863 NM_001800 CDKN2D 4110 8034075 NM_014860 SUPT7L 8051204 NM_000183 HADHB 00062, 00071, 8040639 00280, 01100 NM_001258 CDK3 8010021 NM_005247 FGF3 04010, 04810, 7950036 05200, 05218 NM_007255 B4GALT7 00532, 00534, 8110399 01100 NM_016199 LSM7 03018, 03040 8032480 BC004943 MGC10814 8035551 NR_024593 POM121L10P 8075024 NM_145719 TIGD3 7941255 NM_001164440 ANKRD33B 8104499 NM_174923 CCDC107 8155073 NM_015276 USP22 8013486 NM_001164447 FAM90A10 8144448 NM_133261 GIPC3 8024676 NM_001037984 SLC38A10 8019149 NM_006855 KDELR3 5110 8073015 NM_021944 C14orf93 7977868 NM_005430 WNT1 04310, 04340, 7955170 04916, 05200, 05217 NM_199044 NSUN4 7901219 AK125575 ZNF425 8143708 NM_032344 NUDT22 7940884 NM_018090 NECAP2 7898337 NM_000377 WAS 04062, 04520, 8167334 04666, 04810, 05100, 05130, 05131 NM_001001410 C16orf42 7998449 NM_148172 PEMT 00564, 01100 8013120 NM_001032363 C1orf151 7898574 NM_002949 MRPL12 8010664 NM_012094 PRDX5 4146 7940996 NR_001555 GOLGA2P2Y 8176910 or 8177413 NM_025072 PTGES2 00590, 01100 8164362 NM_138983 OLIG1 8068235 NM_016568 RXFP3 8104781 NM_152914 C17orf103 8013509 NM_014170 GTPBP8 8081676 NM_003513 HIST1H2AB 5322 8124391 NM_003278 CLEC3B 8079305 NM_004637 RAB7A 04144, 04145, 8082431 05146 NM_001144954 C5orf47 8110068 NM_001048183 PHACTR4 7899455 NM_004551 NDUFS3 00190, 01100, 7939825 05010, 05012, 05016 NM_006808 SEC61B 03060, 04141, 8156838 04145, 05110 NM_020199 C5orf15 8114138 NM_030811 MRPS26 8060599 NR_026581 MLF2 7960689 NM_002297 LCN1 8159255 BC104424 FAHD2B 8043682 NM_005714 KCNK7 7949444 NM_001099435 SPDYE5 8133654 BC035374 TCEANC2 7901592 NM_005091 PGLYRP1 8037742 NM_001013653 LRRC26 8165453 NM_182498 ZNF428 8037355 NM_001024678 LRRC24 8153868 or 8153862 NM_001114600 C1orf144 7898328 NM_001614 ACTG1 04145, 04510, 8019183 04520, 04530, 04670, 04810, 05100, 05110, 05130, 05131, 05410, 05412, 05414, 05416 NM_000383 AIRE 04120, 05340 8069037 NR_002911 SNORA71A 8066258 NM_001135580 C19orf71 8024655 NM_145272 C17orf50 8006569 NM_000154 GALK1 00052, 00520, 8018428 01100 AY358234 LOC100129831 8024444 NM_001100418 C19orf60 8027032 NM_020996 FGF6 04010, 04810, 7960407 05200, 05218 NM_001297 CNGB1 04740, 04744 8001615 AK128227 LOC100130236 7919299 or 7919380 NM_002494 NDUFC1 00190, 01100, 8102839 05010, 05012, 05016 NM_198175 NME1 00230, 00240, 8008517 01100 NM_000479 AMH 04060, 04350 8024429 NM_001145250 SP9 8056825 NR_002144 LOC407835 8136065 NM_014110 PPP1R8 7914139 NM_152898 FERD3L 8138450 NR_030170 MIR202 7937148 NM_177398 LMX1A 7921936 NM_178348 LCE1A 7905528 NM_005444 RQCD1 3018 8048340 NM_173806 PDZD9 8000229 NM_006857 SNRNP27 3040 8042495 NM_033644 FBXW11 04114, 04120, 8115765 04310, 04340, 04710, 05131 NM_001164456 FAM90A13 8149204, 8144428, 8144432, 8144436, 8144444 8144424 or 8144440 NM_020070 IGLL1 5340 8074909 NM_005007 NFKBIL1 8118127, 8177967 or 8179249 NM_177542 SNRPD2 3040 8037642 NM_020637 FGF22 04010, 04810, 8023990 05200, 05218 NM_144727 CRYGN 8143949 NM_015568 PPP1R16B 8062557 NM_018250 INTS9 8150014 NM_003517 HIST2H2AC 5322 7905088 NM_032998 DEDD 7921793 NM_173660 DOK7 8093807 NM_015679 TRUB2 8164428 NM_030657 LIM2 8038815 NM_015918 POP5 03008, 03013 7967084 NR_029833 MIR30C1 7900490 NM_001004 RPLP2 3010 7937476 NM_152778 MFSD8 4142 8102730 NM_032595 PPP1R9B 8016628 NM_006686 ACTL7B 8163019 AK291454 UBE2K 4120 8099918 NM_000983 RPL22 3010 7911989 NM_053049 UCN3 7925950 NM_001030047 KLK3 05200, 05215 8030753 NR_003502 ZNRF2P1 8132209 NM_016734 PAX5 8161211 NM_052945 TNFRSF13C 04060, 04672, 8076387 05340 NM_006299 ZNF193 8117655 NM_002764 PRPS1 00030, 00230, 8169240 01100 NM_001024675 C20orf134 8061944 NM_014064 METTL11A 8158544 NM_001002252 ARL6IP4 7959549 NM_004640 DDX39B 03013, 03015, 8178476, 03040 8179750 or 8124926 NM_173514 SLC38A9 8112121 NM_018955 UBB 5012 8005166 NM_001130861 CLDN5 04514, 04530, 8074473 04670, 05160 NM_006432 NPC2 4142 7980146 AB016902 HGC6.3 8130824 NM_000413 HSD17B1 00140, 01100 8007263 NM_001142467 HES4 7911376 NM_181802 UBE2C 4120 8063043 NM_001164453 FAM90A20 8144388 NM_178548 TFAP2E 7900001 NM_032810 ATAD1 7934870 NM_001003682 TMEM200B 7914232 NM_003013 SFRP2 4310 8103254 NM_033178 DUX4 8098732, 8098740, 8098725, 8104122, 8098730, 8098743, 7931665, 7931656, 7931659, 7931662, 7931668 or 7931671 NM_003110 SP2 8008052 NM_021570 BARX1 8162472 NR_002798 NAPSB 8038547 NM_001029865 DBX1 7947129 NM_178138 LHX3 8165083 NM_005202 COL8A2 7914880 NM_001069 TUBB2A 04145, 04540, 8116649 or 05130 8116653 NM_006943 SOX12 8060334 NR_029485 MIR15A 7971661 NM_000986 RPL24 3010 8126450 or 8089249 NM_018158 SLC4A1AP 8041015 NM_012188 FOXI1 8109901 NM_031917 ANGPTL6 8033892 NM_006118 HAX1 7905733 NM_000290 PGAM2 00010, 01100 8139276 NM_024888 LPPR3 8032094 NM_002477 MYL5 04510, 04530, 8093386 04670, 04810 NM_138383 MTSS1L 7997135 NM_004435 ENDOG 4210 8158418 BC008667 PANK2 00770, 01100 8060736 NM_174920 SAMD14 8016615 NM_014581 OBP2B 8180358 NM_176677 NHLRC4 7991898 NM_031157 HNRNPA1 3040 7955890 NR_024420 LOC389634 7960894 NM_032574 DPY30 8051387 NM_138705 CALML6 04020, 04070, 7897026 04114, 04270, 04720, 04722, 04740, 04744, 04910, 04912, 04916, 04970, 04971, 05010, 05214 BC036197 MGC39545 7944972 BC036837 C20orf201 8067812 NM_001111322 DDX54 7958948 NM_016219 MAN1B1 00510, 01100, 8159566 04141 NR_029618 MIR199A2 7922328 NM_001113324 TEN1 8010017 NM_015414 RPL36 3010 8024966 NM_014183 DYNLRB1 8062016 NM_004781 VAMP3 04130, 04145 7897370 NM_002714 PPP1R10 8124756, 8178358 or 8179664 NM_020341 PAK7 04012, 04360, 8064952 04510, 04660, 04810, 05211 NM_080625 C20orf160 8061653 NM_003969 UBE2M 4120 8039805 NM_006232 POLR2H 00230, 00240, 8084488 01100, 03020, 05016 NM_002900 RBP3 7933359 NM_025147 COQ10B 8047217 NM_016932 SIX2 8051949 NM_012210 TRIM32 4120 8157516 NM_019612 IRGC 8029318 NM_013234 EIF3K 8028514 NM_178351 LCE1C 7920193 NM_007167 ZMYM6 7914764 NM_004278 PIGL 00563, 01100 8005157 NM_014688 USP6NL 7926150 NM_006563 KLF1 8034578 NM_207305 FOXD4 8159808 NM_001012710 KRTAP5-10 7942267 NM_020415 RETN 8025278 NM_005225 E2F1 04110, 05200, 8065710 05212, 05214, 05215, 05218, 05219, 05220, 05222, 05223 NM_020839 WDR48 8078834 NM_003332 TYROBP 04380, 04650 8036224 NM_003396 WNT9B 04310, 04340, 8007895 04916, 05200, 05217 NR_026811 AGSK1 7985571, 7985431, 7990952, 7990902 or 7991714 NM_024095 ASB8 7962783 NM_001330 CTF1 04060, 04630 7994961 NM_080865 GPR62 8080158 NM_144582 TEX261 8042566 NM_032328 EFCAB2 7925585 NM_032772 ZNF503 7928529 NM_000194 HPRT1 00230, 00983, 8169984 01100 NM_001009606 HS3ST6 7998634 NM_001100119 XRCC3 3440 7981447 NR_029703 MIR150 8038393 NM_057176 BSND 7901691 NR_003008 SCARNA5 8049297 NM_015913 TXNDC12  480 7916120 NM_006612 KIF1C 8004057 NM_002798 PSMB6 3050 8003953 NM_000684 ADRB1 04020, 04080, 7930627 04144, 04540, 04970, 05414 NM_024812 BAALC 8147756 NM_175078 KRT77 7963502 NM_144736 C2orf56 8041495 NM_002460 IRF4 8116559 NM_001001520 HDGFRP2 8024864 NM_001168479 ARMCX5 8168958 NR_029596 MIR129-1 8135907 NM_005565 LCP2 04380, 04650, 8115734 04660, 04664 NM_001099279 FOXD4L2 8161571, 8155440 or 8161583 NM_198595 AFAP1 8094030 NM_002676 PMM1 00051, 00520, 8076355 01100 NR_003594 REXO1L2P 8151603, 8151607, 8151623, 8151619, 8151627, 8151615 or 8151631 NM_006427 SIVA1 7977288 NM_032152 PRAM1 8033587 NM_001144995 CCDC85C 7981273 NR_002449 SNORA65 8164215 NM_001002909 GPATCH8 8016077 NM_016558 SCAND1 8066031 NM_024335 IRX6 7995674 NM_004788 UBE4A 4120 7944195 NM_021247 PRM3 7999431 NR_024368 FLJ45340 7945344 AK093358 FAM27A 8161442 NM_033467 MMEL1 7911767 NR_002937 C14orf19 7973900 NM_182973 TMPRSS9 8024467 NM_018663 PXMP2 4146 7967789 NM_173728 ARHGEF15 8004842 NM_004610 TCP10 8123374 or 8130787 NM_006013 RPL10 3010 8034416 or 8109821 NM_015999 ADIPOR1 4920 7923503 NM_020209 SHD 8024808 NR_029829 MIR194-2 7949275 NM_198998 AQP12A 8060126 or 8049729 NM_002233 KCNA4 7947270 NM_022098 XPNPEP3 8073311 NM_212550 BLOC1S3 8029640 NM_198949 NUDT1 8131101 NM_006626 ZBTB6 8163999 NM_003795 SNX3 8128683 NR_029663 MIR15B 8083737 NM_207397 CD164L2 7914084 NM_014280 DNAJC8 7899422 NM_001001915 OR2G2 4740 7911207 NM_004930 CAPZB 7913169 NM_015950 MRPL2 8126512 NM_015509 NECAP1 7953715 NM_006894 FMO3  982 7907249 NM_012483 GNLY 8043236 NM_001004333 RNASEK 8004237, 8012000 or 8004241 NM_147196 TMIE 8079426 NR_027850 MTX2 8046573 NM_001037283 EIF3B 3013 8131111 NM_178463 C20orf166 8063914 BC090923 C17orf90 8019238 NM_020825 CRAMP1L 7992302 NM_001080520 DRGX 7933501 NM_153232 EID2 8036749 NM_012186 FOXE3 7901309 NM_213605 ZNF517 8148932 NM_178456 C20orf85 8063601 NM_032547 SCOC 8097521 NM_001170738 IQSEC3 4144 8067820 or 7952893 NM_024591 CHMP6 4144 8010550 NM_014515 CNOT2 3018 7957106 NM_138387 G6PC3 8007561 NM_024326 FBXL15 7930099 NM_007262 PARK7 5012 7897404 NR_001527 TTTY6 8176782 or 8177347 NM_001142588 NFYC 4612 7915345 NM_001080489 GLOD5 8167356 NM_199243 GPR150 8106976 NM_000729 CCK 8086391 NM_024718 C9orf86 8159415 NM_145729 MRPL24 7921121 NM_030662 MAP2K2 04010, 04012, 8032761 04270, 04370, 04540, 04620, 04650, 04660, 04662, 04664, 04720, 04722, 04730, 04810, 04910, 04912, 04916, 05020, 05200, 05211, 05213, 05214, 05215, 05216, 05218, 05219, 05220, 05221, 05223 NM_058190 FAM207A 8180370 or 8069174 NM_001011 RPS7 3010 8005877 or 8040036 NM_014336 AIPL1 8011912 NM_178354 LCE1F 7905517 NM_005470 ABI1 7932616 NM_006357 UBE2E3 04120, 04141 8166124 NR_002182 NACAP1 8147693 NM_001109763 GSG1L 8000467 NM_001085365 MZT2A 8055287 NM_001080468 SYCN 8036699 NM_003365 UQCRC1 00190, 01100, 8087100 04260, 05010, 05012, 05016 NM_153207 AEBP2 7954279 NM_032477 MRPL41 8159687 NM_152911 PAOX 4146 7931582 NM_002488 NDUFA2 00190, 01100, 8114618 05010, 05012, 05016 NM_175895 C12orf61 7964642 NM_004558 NRTN 8024995 NM_198850 PHLDB3 8037315 NR_023343 RNU4ATAC 8044961 NM_004976 KCNC1 7938738 NM_012184 FOXD4L1 8044634 NM_054028 SLC35G5 8020162 NM_006985 NPIP 7999766 or 7993580 NM_138334 JOSD2 8038571 NM_014613 FAF2 8110169 NM_022466 IKZF5 7936826 NM_022731 NUCKS1 7909142 NM_138284 IL17D 7967969 NM_004851 NAPSA 4142 8038556 NM_031292 PUS7L 7962427 NM_017871 CPSF3L 7911486 NM_012476 VAX2 8042532 NM_032343 CHCHD6 8082305 NM_199287 CCDC137 8010629 BC043417 TMEM68 8146480 NR_029714 MIR320A 8149705 NM_207163 LMOD2 8135821 NM_024339 THOC6 3013 7992795 NM_032411 C2orf40 8044143 NM_016491 MRPL37 7901601 NM_003089 SNRNP70 3040 8030199 NM_014360 NKX2-8 7978686 NM_201589 MAFA 04930, 04950 8153409 AK289373 IGHG1 8001104 NM_005583 LYL1 8034608 NM_022375 OCLM 7908347 NM_001006610 SIAH1 04115, 04120, 8001306 04310 NM_172229 KREMEN2 7992758 NM_021996 GBGT1 00603, 01100 8164833 NM_194249 DND1 8114625 NM_001142864 PIEZO1 7997827 NM_178438 LCE5A 7905483 NM_001349 DARS  970 8055445 NM_176806 MOCS2 4122 8112020 NR_024355 BK250D10.8 8073546 NM_024768 CCDC48 8082465 AK093505 SPANXA2-OT1 8175537 or 8170247 NM_024754 PTCD2 8106107 AK125905 LOC100129581 8050113 NM_175619 ZAR1 8094968 NM_001867 COX7C 00190, 01100, 8106776 04260, 05010, 05012, 05016 NM_031492 RBM4B 7949674 NM_153376 CCDC96 8099242 NM_002034 FUT5 00601, 01100 8033064 NM_181462 MRPL55 7924853 NM_012257 HBP1 8135392 NR_027780 HMGXB4 8072645 NM_004822 NTN1 4360 8004880 NM_178454 DRAM2 7918474 NM_015893 PRLH 8049509 NM_024313 NOL12 8072883 NM_006522 WNT6 04310, 04340, 8048445 04916, 05200, 05217 NM_017832 FAM206A 8157144 NM_006947 SRP72 3060 8095230 NM_021948 BCAN 7906205 NM_001164405 BHLHA9 8003633 NM_032830 CIRH1A 3008 7996891 NM_080680 COL11A2 04510, 04512, 8125568 04974, 05146 NM_002622 PFDN1 8114567 NM_002196 INSM1 8061303 NM_002370 MAGOH 03013, 03015, 7916274 03040 NR_024406 LOC732275 8003230 NM_201653 CHIA  520 7903945 AK296222 LOC728093 8112476 or 8105935 NM_004343 CALR 04141, 04145, 8026106 04612, 05142 NM_001003892 DUPD1 7934527 NR_026837 LOC283392 7964976 NM_006274 CCL19 04060, 04062 8160879 NM_014847 UBAP2L 7905700 NM_016396 CTDSPL2 7983335 NM_015944 AMDHD2  520 7992656 NM_144567 ANGEL2 7924190 NM_153270 KLHL34 8171786 NM_080622 ABHD16B 8064203 NM_022753 S100PBP 7899829 AK290103 LOC100287934 7909990 or 7896754 NR_000011 SNORA70 8170863 or 8025498 NM_003968 UBA3 4120 8088718 NM_033257 DGCR6L 8074565 NM_016468 COX16 7979906 NM_030642 APOL5 8072721 NM_002565 P2RY4 4080 8173366 NM_014017 LAMTOR2 7906072 NM_006192 PAX1 8061357 NM_133450 ANKS3 7999177 NM_024302 MMP28 8014282 NM_016166 PIAS1 04120, 04630, 7984453 05160, 05200, 05222 NM_007037 ADAMTS8 7952752 NR_033192 CCDC59 7965200 NM_174895 PCP2 8033414 NM_003279 TNNC2 4020 8066590 NM_001136262 ATXN7L3B 7957242 NM_004108 FCN2 8159211 NM_032829 C12orf34 7958577 NM_139136 KCNC2 7964987 NM_033113 ZNF628 8031489 NM_005687 FARSB  970 8059319 NM_000180 GUCY2D 00230, 04740, 8004763 04744 NM_024309 TNIP2 8099029 NM_014554 SENP1 7962760 NM_001013735 FOXB2 8155942 NM_174922 ADCK5 8148850 NM_032704 TUBA1C 04145, 04540, 7955179 05130 NM_020385 REXO4 8164907 NR_029894 MIR148B 7955906 NM_001040425 U2AF1L4 8036143 NR_029945 MIR423 8006119 U63828 C20orf181 8067754 NM_133636 HELQ 8101467 NM_001102614 SLC35G6 8004428 NM_004549 NDUFC2 00190, 01100, 7950644 05010, 05012, 05016 AY358101 DBF4B 8007673 NM_032842 TMEM209 8142912 NM_001862 COX5B 00190, 01100, 8043718 04260, 05010, 05012, 05016 NM_020535 KIR2DL5A 04612, 04650, 8039884 05332 NM_003443 ZBTB17 4110 7912675 NM_080863 ASB16 8007584 NM_030819 GFOD2 8002082 NM_144576 COQ10A 7956242 NM_001006636 GTDC1 8055606 NM_145178 ATOH7 7933978 NR_029375 WDR83 8026013 NM_005937 MLLT6 8014702 NM_006040 HS3ST4 7994260 NM_203451 SERTM1 7968650 BC146842 FAM26F 8121596 NR_027693 C1orf170 7911371 NM_152353 CLDND2 8038804 NM_003806 HRK 7966746 NM_005169 PHOX2A 7950136 NM_006413 RPP30 03008, 03013 7929116 NM_032259 WDR24 7998280 NM_005861 STUB1 04120, 04141 7992021 NM_178520 TMEM105 8019177 NM_138433 KLHDC7B 8074106 NM_018221 MOBKL1B 8053064 BC043584 C2orf27B 8055291 NM_001166400 MAGEA8 8170412 NM_004421 DVL1 04310, 04330, 7911506 04916, 05200, 05217 NM_001146340 NKX1-2 7936882 NR_027386 GUSBP3 8112560, 8105991, 8177669, 8112469, 8112564 or 8177544 NM_031948 PRSS27 7998843 NM_017619 RNPC3 7903404 NM_017730 QRICH1 8087271 NM_001015072 UFSP1 8141643 NM_005340 HINT1 8113873 NM_033130 SIGLEC10 8038824 NM_001098202 HIC1 8003719 NM_001001502 SNCB 8115948 NM_178516 EXOC3L1 8001953 NM_006757 TNNT3 7937749 NR_029499 MIR26A1 8078663 NR_027028 GUSBP1 8104621 NM_012378 OR8B8 4740 7952404 AF462446 LOC100288144 7981488 NM_173544 FAM129C 8026787 NM_017561 FAM22F 8162479 NM_006070 TFG 05200, 05216 8081316 NM_030754 SAA2 7946983 NM_001001419 SMAD5 4350 8108238 NM_207334 FAM43B 7898653 NM_020884 MYH7B 04530, 05416 8062064 NM_053280 ODF3 7937263 NM_001080475 PLEKHM3 8058509 NM_021221 LY6G5B 8178059 or 8118228 NM_006571 DCTN6 4962 8145660 NM_006754 SYPL1 8142110 NM_016451 COPB1 7946703 NM_152758 YTHDF3 8146637 NM_031274 TEX13A 8174297 NM_001029991 METTL17 7973116 NM_182707 PSG8 8037236 NM_021994 ZNF277 8135497 NM_014042 C11orf51 7950128 NM_145049 UBLCP1 8109597 NM_002590 PCDH8 7971850 NM_005182 CA7  910 7996331 NM_172089 TNFSF12- 8004464 TNFSF13 NM_003403 YY1 7976744 NM_182560 C14orf177 7976635 NM_012182 FOXB1 7984011 NM_014302 SEC61G 03060, 04141, 8139706 04145, 05110 NM_005262 GFER 7992439 NM_001001481 UBE2W 4120 8151401 NM_001007561 IRGQ 8037352 NM_199290 NACA2 8017259 NR_030174 MIR494 7976834 NM_207379 TMEM179 7981490 NR_003129 RNF5P1 8178188 or 8150356 NM_015953 NOSIP 8038395 BC017770 RBM8A 03013, 03015, 7904751 03040 NM_017964 SLC30A6 8041257 NM_030761 WNT4 04310, 04340, 7913547 04916, 05200, 05217 NM_005406 ROCK1 04062, 04270, 8020382 04310, 04350, 04360, 04510, 04670, 04810, 05130, 05131 NM_017945 SLC35A5 8081667 NM_173502 PRSS36 8001014 NM_024766 CAMKMT 8041745 NM_181706 DNAJC24 7939093 NM_033251 RPL13 3010 8180283 or 8180284 NM_178525 ACTL9 8033662 NM_006351 TIMM44 8033465 NM_181711 GRASP 7955578 NM_021223 MYL7 04510, 04530, 8139307 04670, 04810 NM_052936 ATG4A 4140 8169272 NM_007108 TCEB2 04120, 05200, 7998852 05211 NM_080594 RNPS1 03013, 03015 7998774 NM_178167 ZNF598 7998679 NM_001004453 OR1L6 4740 8157688 NR_000015 SNORD55 7901046 NM_016093 RPL26L1 3010 7945740 NM_001694 ATP6V0C 00190, 01100, 7992646 04142, 04145, 04966, 05110, 05120, 05323 NM_024112 C9orf16 8158177 AB001736 IGLJ3 7981730 NM_001136046 ZMYND15 8003926 NM_024887 DHDDS  900 7899173 NR_015370 EPB41L4A-AS1 8107321 NM_000265 NCF1 04062, 04145, 8140227 or 04380, 04666, 8133518 04670, 05140 NM_002792 PSMA7 3050 8067382 NM_199186 BPGM 00010, 01100 8136341 NM_024316 LENG1 8039139 NM_021134 MRPL23 7937763 NM_017610 RNF111 7983953 NM_203434 IER5L 8164554 NM_080607 VSTM2L 8062427 NM_022573 TSPY2 8176419 NR_029603 MIR139 7950195 NM_080606 BHLHE23 8067585 NM_194358 RNF41 4144 7964021 NM_016378 VCX2 8171240 NM_015417 SPEF1 8064751 NM_021231 C19orf29 8024682 NM_020395 INTS12 8102162 NM_018225 SMU1 8160622 NM_173209 TGIF1 8180316, 8180319, 8180318 or 8180317 NM_032319 PRADC1 8053004 NM_145055 C18orf25 8021113 NM_002818 PSME2 03050, 04612 7978123 NR_029891 MIR326 7950490 NM_001303 COX10 00190, 00860, 8005089 01100 NM_152492 CCDC27 7897196 NM_002235 KCNA6 7953264 NM_153368 GJD4 7933073 NM_016390 C9orf114 8164481 NM_173829 SREK1IP1 8112337 NM_172347 KCNG4 8003149 NM_002620 PF4V1 04060, 04062 8095694 NM_015506 MMACHC 4977 7901102 NM_000626 CD79B 4662 8017511 NM_080650 ATPBD4 7987369 NM_016145 C19orf56 8034448 NM_016399 TRIAP1 7967056 NM_005803 FLOT1 4910 8124828, 8178419 or 8179688 NM_002710 PPP1CC 04114, 04270, 7966368 04510, 04720, 04810, 04910 NM_003090 SNRPA1 3040 7991598 NM_015530 GORASP2 8046306 NM_052846 EMILIN3 8066294 NM_053006 TSSK2 8071196 NM_003134 SRP14 3060 7987449 NM_014765 TOMM20 7925174 NM_007026 DUSP14 4010 8006736 NM_005125 CCS 5014 7941685 NM_178161 PTF1A 7926674 BC016613 C16orf11 7991893 NM_018471 ZC3H15 8057561 NM_007265 ECD 7934301 NM_017521 FEV 8059014 NM_024041 SCNM1 7905355 NM_020192 C7orf36 8132399 NM_018403 DCP1A 3018 8088128 NM_199350 C9orf50 8164562 NM_182577 ODF3L2 8032051 NM_001001657 OR2Y1 4740 8116482 BC126459 C10orf95 7936023 NM_025108 C16orf59 7992614 NM_133455 EMID1 8072189 NR_003587 MYO15B 8009873 AK023602 CEACAM21 8037043 NM_001025200 CTRB2 8002845 NM_001037637 BTF3 8106181 NM_213622 STAMBP 4144 8042772 NM_004826 ECEL1 8059748 NM_000198 HSD3B2 00140, 01100 7904408 NM_172341 PSENEN 04330, 05010 8027996 NM_152344 LSM12 8015908 or 8150206 NR_027392 INTS4L2 8133095 NM_004914 RAB36 8074880 AK124070 LOC400707 8029829 NM_018233 OGFOD1 7995755 NM_001078166 SRSF1 3040 8016898 NM_002434 MPG 3410 7991742 NM_152704 FAM123A 7970648 NM_001038640 GOLGA6A 7984985 NM_178449 PTH2 8038362 NM_021934 C12orf44 7955606 NR_029614 MIR182 8142880 NM_015161 ARL6IP1 7999834 NM_001099692 EIF5AL1 7934753, 7928600 or 7928630 NM_024409 NPPC 8059739 AY956766 HSP90AB5P 8080987 NM_032028 TSSK1B 8113573 NM_003574 VAPA 4530 8020129 NM_001170330 C4orf3 8102518 NM_007176 C14orf1 7980309 NM_002155 HSPA6 03040, 04010, 7906764 04141, 04144, 04612, 05145 NM_005332 HBZ 7991754 NM_001080434 LMTK3 8038093 NM_003352 SUMO1 3013 8058335 NM_022468 MMP25 7992811 NM_000938 POLR2B 00230, 00240, 8095269 01100, 03020, 05016 AK022260 LOC401052 8085272 NM_205848 SYT6 7918716 NM_022756 MEAF6 7914996 NM_001137550 LRRFIP1 8049538 NM_020943 CWC22 8057441 NM_080596 HIST1H2AH 5322 8117543 NR_033460 PAGE3 8173168 NM_153812 PHF13 7897322 NM_007243 NRM 8178399, 8179683 or 8124806 NM_003172 SURF1 8164896 NM_001123355 PPP6C 8164155 NM_198285 WDR86 8143941 NM_012403 ANP32C 8103518 NM_001906 CTRB1 04972, 04974 7997264 NM_080662 PEX11G 4146 8033385 NM_024811 CPSF7 3015 7948574 NR_001548 TTTY11 8177085 NM_002144 HOXB1 8016433 BC119675 FAM27E3 8155569, 8161426 or 8161437 AK095821 LTB 04060, 05323 8118147, 8124950, 8178512 or 8179768 NM_018188 ATAD3A 7896952 NR_002226 INGX 8173486 NM_197960 DPP8 7989806 NR_028409 LINC00207 8073698 NM_201397 GPX1 00480, 00590, 8087405 05014, 05016 NM_052970 HSPA12B 8060660 NR_002992 SNORA7B 8090565 NM_005628 SLC1A5 4974 8029854 NM_003973 RPL14 3010 8078984 NR_029620 MIR203 7977214 NM_182572 ZSCAN1 8031847 NM_032110 DMRTA2 7915991 AK126112 FLJ44124 8131042 NM_175609 ARFGAP1 4144 8064042 NM_018466 ALG13 00510, 01100 8169412 NM_004379 CREB1 04380, 04612, 8047839 04916, 04962, 05016, 05215 NM_004801 NRXN1 4514 8052091 NM_001965 EGR4 8053022 NM_022454 SOX17 4310 8146462 NM_198570 VWC2 8132805 NR_002961 SNORA22 8133106 NM_153029 N4BP1 8001317 NM_012179 FBXO7 8072610 NM_057093 CRYBA2 8059019 NM_005507 CFL1 04360, 04666, 7949496 04810 NM_025215 PUS1 7959986 NM_003868 FGF16 04010, 04810, 8168463 05200, 05218 NM_024798 SNX22 7984174 NM_004095 EIF4EBP1 03013, 04012, 8145889 04150, 04910, 05221 NM_007254 PNKP 8038458 NM_012282 KCNE1L 8174469 NM_016239 MYO15A 8005328 NM_003322 TULP1 8125903 NM_003456 ZNF205 7992845 NM_020994 CTAG2 8176159 NM_203400 RPRML 8016320 NM_000797 DRD4 4080 7937433 NM_001013620 ALG10B 00510, 01100 7954789 NM_058219 EXOSC6 3018 8002344 NR_029687 MIR152 8016400 BC011833 C19orf52 8025783 AL137273 DKFZP434I0714 8097811 NM_018120 ARMC1 8151066 NR_028082 COL18A1-AS1 8070905 NR_029693 MIR125A 8030846 NM_014233 UBTF 8015969 NM_199184 C6orf108 8126524 NM_003015 SFRP5 4310 7935528 NM_014357 LCE2B 7905505 NM_019849 SLC7A10 8035993 NM_005061 RPL3L 3010 7998643 NM_015911 ZNF691 7900624 NM_182706 SCRIB 8153497 NM_198458 ZNF497 8039759 NM_015702 MMADHC 8055672 NM_004330 BNIP2 7989323 NM_006913 RNF5 4141 8118535 or 8179472 NM_001136002 TMEM229A 8142685 NR_003496 SNORD115-27 7982060 NM_016111 TELO2 7992271 NM_003144 SSR1 4141 8123767 NM_001013658 PTX4 7998538 NM_004675 DIRAS3 7916853 NM_001127266 TMEM129 8098916 NM_013403 STRN4 8037816 NM_199135 FOXD4L3 8155661 NM_022374 ATL2 8051589 NM_024740 ALG9 00510, 01100 7951633 NM_016068 FIS1 8141717 NM_013286 RBM15B 8080093 NM_015722 CALY 7937200 NM_001007540 CDHR4 8087481 NM_020201 NT5M 00230, 00240, 8005247 00760, 01100 NR_002326 SNORA64 7998666 NM_152760 SNX32 7941408 NM_001032288 UBE2V1 8180402 NM_001077394 DPH5 7918034 NM_033176 NKX2-4 8065327 NM_178545 TMEM52 7911634 NM_080476 PIGU 00563, 01100 8065762 NM_014008 CCDC22 8167457 NM_017510 TMED9 8110392 NM_022077 MANBAL 8062371 NM_021938 CELF5 8024605 NM_001774 CD37 4640 8030277 NM_001749 CAPNS1 8028172 NM_001130064 GAP43 8081810 NM_015667 FAM75A7 8161341, 8161471, 8155383 or 8155371 NM_138493 CCDC167 8126095 NM_004547 NDUFB4 00190, 01100, 8081945 or 05010, 05012, 8093314 05016 NM_015659 RSL1D1 7999520 NM_014383 ZBTB32 8027947 NM_001001888 VCX3B 8165890 NM_173825 RABL3 8089867 NM_018690 APOBR 7994353 NM_002777 PRTN3 8024048 NM_001001660 LYRM5 7954460 NM_000967 RPL3 3010 8076209 NM_006917 RXRG 03320, 04920, 7921955 05200, 05216, 05222, 05223 NM_182563 C16orf79 7998749 NM_021197 WFDC1 7997582 NM_001039165 MRGPRE 7945859 NR_015343 LOC389458 8131296 NM_145057 CDC42EP5 8039273 NM_016069 PAM16 7999112 NM_203374 ZNF784 8039530 NM_002952 RPS2 3010 7998655 or 8013348 NM_003217 TMBIM6 7955277 NM_145665 SPANXE 8175543 NR_004845 LOC644936 8112883 NM_007148 RNF112 8005586 NM_000286 PEX12 4146 8014264 NM_152735 ZBTB9 8118721 NM_198153 TREML4 8119427 NM_005053 RAD23A 03420, 04141 8026122 AK056484 LOC441204 8131965 AB016901 C6orf123 8123405 NR_004390 SNORA57 7940667 NM_001144932 PSMB5 3050 7977879 NM_130760 MADCAM1 04514, 04672 8023941 NM_198469 MORN5 8157632 NM_032120 C7orf64 8134211 NM_013275 ANKRD11 7997907 or 8170322 NM_145702 TIGD1 8059770 NM_018082 POLR3B 00230, 00240, 7958275 01100, 03020, 04623 NM_001001414 NCCRP1 8028600 NM_198407 GHSR 4080 8092165 NM_001028 RPS25 3010 7939068 NM_025224 ZBTB46 8067743 NR_027393 INTS4L1 8133074 NM_002412 MGMT 7931379 NM_018973 DPM3 00510, 01100 7920633 NM_176875 CCKBR 04020, 04080, 7938090 04971 NM_144703 LSM14B 8063835 NM_080819 GPR78 8094093 NM_175769 TCF23 8040827 NM_139073 SPATA3 8049007 NM_001007533 DYSFIP1 8019243 NM_001313 CRMP1 8099172 NM_012478 WBP2 8018482 NM_014209 ETV2 8027920 NM_017612 ZCCHC8 7967287 NM_001516 GTF2H3 03022, 03420 7959623 NM_021138 TRAF2 04010, 04141, 8159476 04210, 04380, 04622, 04920, 05160, 05200, 05222 NM_021926 ALX4 7947563 NM_001136156 ZNF507 8027439 NM_207409 C6orf126 8118990 NR_002962 SNORA23 7938329 AK095315 FBXO9 8120269 or 8127128 NM_181842 ZBTB12 8125201 or 8178683 NM_015358 MORC3 8068460 NM_024019 NEUROG2 8102368 NM_001145408 NONO 8168280 NM_031954 KCTD10 7966202 NM_207360 ZC3H12D 8130073 NM_004725 BUB3 4110 7931187 NM_001236 CBR3 00590, 01100 8068413 NM_015426 POC1A 8087839 NM_023018 NADK 00760, 01100 7911600 NM_176801 ADD1 8093643 NM_006367 CAP1 7900382 NM_015846 MBD1 8023323 NM_024815 NUDT18 8149646 NM_012139 SERGEF 7946933 NM_007373 SHOC2 7930470 NM_003508 FZD9 04310, 04916, 8133335 05200, 05217 NM_006090 CEPT1 00564, 00565, 7903908 01100 NM_199482 PHOCN 8047228 NM_178310 SNAI3 8003344 NR_002914 SNORD62A 8158862 or 8158864 NM_014468 VENTX 7931556 AK094477 LOC100129113 8074307 NM_003308 TSPY1 8176517, 8176484 or 8176544 NM_015381 FAM19A5 8073929 NR_002563 SNORD27 7948906 NM_001416 EIF4A1 3013 8004497 NM_013318 PRRC2B 8164649 NM_001014283 DCUN1D2 7972912 NM_207395 ZNF324B 8031949 NM_198446 C1orf122 7900192 NM_001170741 FAM22G 8156620 NM_004219 PTTG1 04110, 04114 8109639 NM_018202 TMEM57 7899018 NM_080723 NRSN1 8117178 NM_018697 LANCL2 8132897 NM_181837 ORC3 4110 8121043 NR_027020 ANKRD30BL 8055297 NM_153443 KIR3DL3 4612 8031260 NM_173470 MMGT1 8175360 NM_025220 ADAM33 8064686 NM_000399 EGR2 7933872 NM_003857 GALR2 4080 8010030 AK097109 LOC100131860 7991047 NM_152578 FMR1NB 8170353 NM_003690 PRKRA 8057034 NM_015113 ZZEF1 8003846 NM_203422 LRRN4CL 7948794 NM_001099338 FAM22A 7928653 or 7928645 NM_030930 UNC93B1 8138147 or 8094144 NM_001136263 C2CD4C 8032034 NM_003450 ZNF174 7992897 AK056275 FLJ31713 8163533 NM_001080493 ZNF823 8034315 NM_022063 FAM204A 7936578 NM_177965 C8orf37 8151898 NM_006236 POU3F3 8044109 NM_173506 LYPD4 8037061 NM_001004310 FCRL6 7906475 NM_012192 FXC1 7938111 NM_006136 CAPZA2 8135625 NM_033258 GNG8 4062 8037785 NM_175876 EXOC8 7925043 NM_138690 GRIN3B 4080 8024100 NM_031890 CECR6 8074223 NM_130468 CHST14  532 7982745 NM_006328 RBM14 7941694 NM_001420 ELAVL3 8034263 NM_014276 RBPJL 4330 8062948 NM_183375 PRSS48 8097794 NM_016512 SPAG11B 8144460 NM_012473 TXN2 8075778 NM_020143 PNO1 8052719 NM_018652 GOLGA6B 7984961, 7984662 or 7985221 NM_004911 PDIA4 04141, 05110 8143684 NM_007208 MRPL3 8090678 NM_005547 IVL 7905533 NM_001009994 RIPPLY2 8120937 NM_003505 FZD1 04310, 04916, 8134117 05200, 05217 NM_174889 NDUFAF2 8105499 NM_002506 NGF 04010, 04210, 7918869 04722 NM_022157 RRAGC 7915160 NR_004387 SCARNA10 7953383 NM_001864 COX7A1 00190, 04260, 8036284 05010, 05012, 05016 NM_004314 ART1 7937882 NM_001695 ATP6V1C1 00190, 01100, 8147724 04145, 04966, 05110, 05120, 05323 NM_023007 JMJD4 7924823 NM_002377 MAS1 04080, 04614 8123176 NM_001142648 SAR1A 4141 7934122 NM_020971 SPTBN4 8028806 NM_004470 FKBP2 7940914 NM_002032 FTH1  860 8170360 NM_001017928 CCDC58 8089988 NM_001098169 BSX 7952321 NM_001145030 C3orf77 8079167 NM_006294 UQCRB 00190, 01100, 8151909 04260, 05010, 05012, 05016 NM_198492 CLEC4G 8033433 NM_138364 PRMT10 8103079 NM_006362 NXF1 03008, 03013, 7948839 03015 NM_001130963 TMEM194A 7964347 NM_144720 JAKMIP1 8099200 NM_031209 QTRT1 8025728 NM_015092 SMG1 3015 8000687 NM_014637 MTFR1 8146649 NM_003837 FBP2 00010, 00030, 8162492 00051, 01100, 04910 NM_001172129 HCK 04062, 04666 8061668 NR_003260 DNM1P46 7986426 NM_016013 NDUFAF1 7987642 NM_004831 MED26 8035187 NM_022728 NEUROD6 8138882 NM_153442 GPR26 7931199 NM_152864 NKAIN4 8067602 NM_002309 LIF 04060, 04630 8072314 NM_003951 SLC25A14 8169904 NM_033341 BIRC8 8039078 NM_018698 NXT2 03008, 03013, 8169352 03015 NM_198353 KCTD8 8100070 NM_001127258 HHIPL1 7976669 NR_027001 LOC388152 7991159 or 7991088 NM_013270 PRSS50 8086660 NM_001105572 PLA2G2C 00564, 00565, 7913235 00590, 00591, 00592, 01100, 04010, 04270, 04370, 04664, 04730, 04912, 04972, 04975, 05145 NM_014846 KIAA0196 8152782 NM_005205 COX6A2 00190, 01100, 8001041 04260, 05010, 05012, 05016 NM_130777 XAGE2 8167693 or 8172749 NR_024151 HSPA7 7906775 AY358690 EEF1D 8153457 NM_005800 USPL1 7968333 NM_016486 TMEM69 7901135 NM_020649 CBX8 8019010 NM_152516 COMMD1 8042207 NM_015933 CCDC72 7899346 NM_016125 RNFT1 8017162 NM_001485 GBX2 8059864 NM_032730 RTN4IP1 8128606 NM_001143938 ZNF534 8030939 NM_017622 C17orf59 8012397 AK313893 CCDC82 7951157 NM_013334 GMPPB 00051, 00520, 8087461 01100 NM_181788 H1FNT 7955112 NM_023039 ANKRA2 8112596 NM_172239 REXO1L1 3008 8151609 NM_032834 ALG10 00510, 01100 7954777 NM_182546 VSTM2A 8132851 NM_015871 ZNF593 7899096 NR_002912 SNORA67 8004508 NM_002860 ALDH18A1 00330, 01100 7935230 NM_001166222 CARNS1 7941890 NM_022662 ANAPC1 04110, 04114, 8054437 or 04120, 04914 8043322 NM_025263 PRR3 8117922 NM_139062 CSNK1D 04340, 04540, 8019463 04710 NM_080864 RLN3 8026265 NR_002450 SNORD68 7997940 NM_003224 ARFRP1 8067727 NM_001145928 SAP130 8055104 NM_006741 PPP1R1A 4720 7963826 NM_139174 ADAD2 7997569 NM_199193 BRE 8041031 NM_021190 PTBP2 7903188 NM_005634 SOX3 8175528 NM_021211 ZBED5 7946635 NM_015267 CUX2 7958726 NM_020755 SERINC1 8129317 NM_144632 TMEM182 8044094 NM_006036 PREPL 8051928 NM_015634 KIAA1279 7927955 NM_004450 ERH 7979864 NM_015676 C14orf109 7976333 NM_014655 SLC25A44 7906128 NM_018641 CHST12 00532, 00920 8131135 NM_004793 LONP1 8033002 NM_139209 GRK7 04062, 04144, 8083129 04744 NM_001641 APEX1 3410 7973056 NM_178510 ANKK1 7943943 NM_182520 C22orf15 8071745 NM_014675 CROCC 7898377 NM_001013632 TCTEX1D4 7915609 NM_001080469 FBXO46 8037647 NR_026833 LOC400940 8040077 NM_006137 CD7 4640 8019478 NM_002987 CCL17 04060, 04062 7996034 NM_012112 TPX2 8061579 NM_015910 WDPCP 8052598 NM_001003938 HBM 7991758 NR_029857 MIR302B 8102406 NM_003198 TCEB3 7898881 NM_001690 ATP6V1A 00190, 01100, 8081740 04145, 04966, 05110, 05120, 05323 NM_005153 USP10 7997633 NR_029495 MIR23A 8034698 NM_001077621 VPS37D 4144 8133339 NM_001100600 MMD2 8137931 NR_027284 LOC441177 8123334 NM_032819 ZNF341 8061946 NM_017438 SETD4 8070215 NM_005744 ARIH1 7984641 NM_030571 NDFIP1 8108861 NM_014275 MGAT4B 00510, 01100 8116316 NR_002922 SNORA13 8107326 NR_024532 ALG2 00510, 01100 8162827 NM_016172 UBAC1 8165064 NM_001023560 ZNF187 8117667 AK125652 NIF3L1 8047370 NM_017638 MED18 7899448 NM_032339 C17orf37 8014882 NM_152494 DCST1 7905862 NM_001001973 ATP5C1 00190, 01100, 7926084 05010, 05012, 05016 NM_016237 ANAPC5 04110, 04114, 7967149 04120, 04914 NM_030578 B9D2 8037018 NM_021970 LAMTOR3 4010 8101925 NM_002568 PABPC1 03013, 03015, 8152079 03018 NM_001164416 H2BFM 5322 8169080 NM_003353 UCN 8051061 NM_003477 PDHX 1100 7939329 NM_181806 AASDH 8100478 NM_001081461 JMJD6 8018793 NM_153358 ZNF791 8026007 NM_006077 MICU1 7934255 NM_001005470 OR4B1 4740 7939865 NM_022101 CXorf56 8180338 NM_012318 LETM1 8098924 NM_018241 TMEM184C 8097704 NR_026961 LOC284837 8070708 NM_001008536 TCHHL1 7920135 NM_203348 MGC50722 8180347 NM_016091 EIF3L 8072946 NM_018129 PNPO 00750, 01100 8008064 NM_138277 C6orf25 8178074 NR_002950 SNORA2A 7962827 NR_033338 C17orf70 8019194 L23320 RFC1 03030, 03420, 8165672 03430 NM_152888 COL22A1 8153101 NR_026686 PDIK1L 7899087 NM_001004341 ETV3L 7921222 NM_014885 ANAPC10 04110, 04114, 8103005 04120, 04914 NM_025134 CHD9 8001402 NM_001130059 ATF7 7963698 NM_002484 NUBP1 7993185 NM_001024594 C1orf53 7908525 NM_005897 IPP 7915775 NM_032878 ALKBH6 8036242 NM_000144 FXN 8155699 NM_032802 SPPL2A 7988753 NM_001051 SSTR3 4080 8075906 NM_016293 BIN2 7963289 NM_147191 MMP21 7936928 NM_013239 PPP2R3B 3015 8176986 or 8171087 NM_001080483 TMEM8C 8164931 NM_002796 PSMB4 3050 7905395 NM_032663 USP30 7958439 NM_172140 IL29 04060, 04630 8028613 NM_014018 MRPS28 8151471 AK299337 FAM65C 8066985 NM_148961 OTOS 8060094 NM_001134875 C14orf80 7977418 NM_001003703 ATP5J 00190, 01100, 8069633 05010, 05012, 05016 NM_032048 EMILIN2 8019912 NM_183401 RNF14 8108847 NM_030943 AMN 7977033 NM_001827 CKS2 8156290 NR_003049 SNORD32B 8117746 NM_053284 WFIKKN1 7991927 NM_006830 UQCR11 00190, 01100, 8032284 04260, 05010, 05012, 05016 NM_016222 DDX41 8116096 NM_001326 CSTF3 3015 7947396 NM_003434 ZNF133 8061154 NM_018049 PLEKHJ1 8032455 NR_027686 LINC00176 8064242 NM_012183 FOXD3 7901913 BC071695 C11orf71 7951781 NR_024209 RNF185 8075477 NM_000738 CHRM1 04020, 04080, 7948912 04810 NM_022465 IKZF4 7956105 NM_004420 DUSP8 4010 7945641 NM_004550 NDUFS2 00190, 01100, 7906703 05010, 05012, 05016 NM_018691 FAM114A2 8115375 NM_173680 ZNF775 8137228 NM_138414 CCDC101 7994362 NM_178554 KY 8090872 NM_178842 CERS3 7991546 NM_152414 BHLHE22 8146645 NM_005370 RAB8A 4972 8026520 NR_001543 TTTY14 8177217 NM_016585 THEG 8032023 NM_173575 STK32C 7937089 NM_004479 FUT7 00514, 00601, 8165398 01100 NM_078483 SLC36A1 4974 8109350 NM_016617 UFM1 7968670 NM_017838 NHP2 3008 8116168 NM_000947 PRIM2 00230, 00240, 8120411 01100, 03030 BC063891 C1orf201 7913787 NM_001010903 C6orf222 8125980 NM_002751 MAPK11 04010, 04370, 8076978 04380, 04620, 04621, 04622, 04660, 04664, 04670, 04722, 04912, 04914, 05014, 05120, 05131, 05140, 05142, 05145, 05160 NM_001002255 SUMO4 3013 8122684 NM_198989 DLEU7 7971663 BC063653 LOC441239 8139828 NM_194328 RNF38 8161192 NM_007097 CLTB 04142, 04144, 8115918 05016, 05100 NM_152665 TCTEX1D1 7902158 NM_020679 MIF4GD 8018343 NM_014736 KIAA0101 7989647 NM_148886 SMCR7 8005435 NM_139286 CDC26 04110, 04114, 8163481 04120, 04914 NM_138771 CCDC126 8131871 NM_000252 MTM1 8170428 NM_020862 LRFN1 8036707 NM_173860 HOXC12 7955852 NM_001169 AQP8 4976 7994252 NM_194248 OTOF 8050942 NM_019070 DDX49 8027100 NR_027138 C11orf36 7937868 NM_032539 SLITRK2 8170307 NM_016310 POLR3K 00230, 00240, 7998129 01100, 03020, 04623 NR_004388 SCARNA14 7989922 NM_032556 IL1F10 8044563 NM_016215 EGFL7 8159354 NM_014402 UQCRQ 00190, 01100, 8107998 04260, 05010, 05012, 05016 NM_016581 ECSIT 4010 8034286 NM_005632 SOLH 7991877 NM_152779 GLIPR1L1 7957245 NM_003807 TNFSF14 4060 8033248 NR_027241 LOC388796 8066247 NM_031941 USHBP1 8035254 NM_020967 NCOA5 8066668 NM_153477 UXT 8172358 NM_025029 MZT2B 8045142 NM_001887 CRYBB1 8075118 NR_027283 LOC440461 8009430 NM_005171 ATF1 7955425 NR_024075 EMR4P 8033332 NM_000409 GUCA1A 04740, 04744 8119515 NM_001080461 UNCX 8131087 NM_001031834 RAB40AL 8169006 NM_014669 NUP93 3013 7995843 NM_014647 KIAA0430 7999642 NM_001852 COL9A2 4974 7915297 NM_003544 HIST1H4B 5322 8124385 NM_001037125 UNKL 7998466 NM_174937 TCERG1L 7937059 BC028365 C7orf62 8140852 NM_198317 KLHL17 7896779 NM_014044 UNC50 8043820 NM_001436 FBL 3008 8036777 NM_138568 EXOC3L2 8037513 NM_018011 ARGLU1 7972723 BC001912 FAM195A 7991932 NM_002688 SEPTIN5 5012 8071259 NM_001991 EZH1 8015685 NM_080651 MED30 8148022 NM_001099784 FBXL19 7994967 NM_030755 TMX1 7974303 NR_026925 LOC151174 8059985 NR_031565 MIR320C1 8020419 NM_030895 ZNF696 8148615 NR_027238 LOC654342 8053722 NR_026974 C8orf77 8148951 NM_012384 GMEB2 8067709 NM_138454 NXNL1 8035315 NR_003004 SCARNA22 8093576 NM_172251 MRPL54 8024708 NM_001005188 OR6X1 4740 7952373 NM_013245 VPS4A 4144 7996919 NM_012267 HSPBP1 4141 8039440 NM_002795 PSMB3 3050 8006812 NM_021066 HIST1H2AJ 5322 8124518 NM_001344 DAD1 00510, 01100, 7977775 04141 NM_003348 UBE2N 4120 7965471

In one embodiment, a variant of a nucleotide sequence SEQ ID NO: X is a nucleotide sequence comprising at least 25 contiguous nucleotides, preferably of at least 50, 100, 150, 200 or at least 500 contiguous nucleotides of said nucleotide sequence SEQ ID NO: X.

In another embodiment, a variant of a nucleotide sequence SEQ ID NO: X is a nucleotide sequence comprising the nucleotide sequence SEQ ID NO: X and additional nucleic acids in 3′ and/or 5′ of SEQ ID NO: X, wherein the number of additional nucleic acids ranges from 1 to 500, preferably from 1 to 200, more preferably from 1 to 100 nucleotides.

In another embodiment, a variant of a nucleotide sequence SEQ ID NO: X is a nucleotide sequence that typically differs from said nucleotide sequence SEQ ID NO: X in one or more substitutions, deletions, additions and/or insertions. In one embodiment, said substitutions, deletions, additions and/or insertions may affect 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleic acids.

In another embodiment, a variant of a nucleotide sequence SEQ ID NO: X is a nucleotide sequence of at least 25, preferably of at least 50, 100, 150, 200, 300, 400, 500, 1000, 1500, 2000 or 3000 nucleotides having at least 75%, 80%, 90%, 95%, or at least 96%, 97%, 98%, 99% identity with the nucleotide sequence SEQ ID NO: X.

The term “identity” or “identical”, when used in a relationship between the sequences of two or more polypeptides, refers to the degree of sequence relatedness between polypeptides, as determined by the number of matches between strings of two or more amino acid residues. “Identity” measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (i.e., “algorithms”). Identity of related polypeptides can be readily calculated by known methods. Such methods include, but are not limited to, those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M. Stockton Press, New York, 1991; and Carillo et al., SIAM J. Applied Math. 48, 1073 (1988). Preferred methods for determining identity are designed to give the largest match between the sequences tested. Methods of determining identity are described in publicly available computer programs. Preferred computer program methods for determining identity between two sequences include the GCG program package, including GAP (Devereux et al., Nucl. Acid. Res. \2, 387 (1984); Genetics Computer Group, University of Wisconsin, Madison, Wis.), BLASTP, BLASTN, and FASTA (Altschul et al., J. MoI. Biol. 215, 403-410 (1990)). The BLASTX program is publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul et al. NCB/NLM/NIH Bethesda, Md. 20894; Altschul et al., supra). The well-known Smith Waterman algorithm may also be used to determine identity.

In one embodiment of the invention, a fragment is a nucleotide sequence of at least 25 nucleotides, preferably of at least 50, 100, 150, 200 or at least 500 nucleotides. In one embodiment of the invention, a fragment of a sequence SEQ ID NO: X is a sequence of at least 25 contiguous nucleotides, preferably of at least 50, 100, 150, 200 or at least 500 contiguous nucleotides of SEQ ID NO: X.

In one embodiment, an equivalent of a nucleotide sequence SEQ ID NO: X, preferably of a gene having the sequence SEQ ID NO: X, is a nucleotide sequence, preferably a gene involved in the same pathway than the nucleotide sequence SEQ ID NO: X. A list of pathways and proteins involved in these pathways is available, for example, on the websites http://www.genome.jp/kegg/pathway.html or http://www.mybiosource.com/page.php ?name=pathways.

In another embodiment, cycling hypoxia markers are selected from the list of the 651 cycling hypoxia markers of Table 2 below, as well as their variants, fragments or equivalents. Table 2 comprises cycling hypoxia markers identified in the conditions of the Example and presenting a p-value after FDR correction lower than 0.01.

TABLE 2 GeneBank Name of the Accession Number marker Pathways Probeset NR_002312 RPPH1 7977507 BC018448 MALAT1 7949410 NR_003287 RN28S1 7942875 or 8059576 AF284753 UIMC1 7911343 or 8165703 NM_014248 RBX1 03420, 04110, 8073334 04114, 04120, 04141, 04310, 04350, 04710, 05200, 05211 NM_177987 TUBB8 04145, 04540, 7911355 05130 NM_170601 SIAE 7944867 NM_001012708 KRTAP5-3 7945652 NR_029710 MIR193A 8006321 NM_000981 RPL19 3010 8006845 NM_012217 TPSD1 7992191 NM_003792 EDF1 8165309 BC013044 DNAJA2 4141 7995379 NR_029824 MIR128-2 8078527 NM_004352 CBLN1 8001329 NM_001017 RPS13 3010 7946812 NM_001037160 CYS1 8050232 NM_003731 SSNA1 8159609 NM_006160 NEUROD2 8014865 NM_001417 EIF4B 03013, 04150 7963575 NM_017854 TMEM160 8037853 NM_016057 COPZ1 7955896 NM_152568 NKX6-3 8150433 NM_016170 TLX2 8042896 NR_002715 RN7SL1 8040338 NM_016564 CEND1 7945536 AK302042 LOC440518 8027343 NM_014206 C11orf10 7948606 NR_033335 SNORA70G 7964830 NM_003094 SNRPE 3040 8160033 or 7908988 NM_012322 LSM5 03018, 03040 8138912 NM_145232 CTU1 4122 8038782 NR_029583 MIR197 7903717 NM_032231 FAM96A 7989611 NR_024583 POM121L8P 8071168 NM_007241 SNF8 4144 8016508 NM_000307 POU3F4 8168567 NM_013299 SAC3D1 7941122 NM_005608 PTPRCAP 7949792 NM_006327 TIMM23 7927548 NM_016424 LUC7L3 8016733 NM_144615 TMIGD2 8032782 NM_001135086 PRSS41 7992716 NM_003512 HIST1H2AC 5322 8117372 NM_000863 HTR1B 4080 8127692 NM_145203 CSNK1A1L 04310, 04340 7971071 NR_000009 SNORD4B 8005957 NM_001080113 C14orf184 7980859 AK123383 LOC642648 8076747 NM_032479 MRPL36 8110861 NM_031210 SLIRP 7975989 NM_023002 HAPLN4 8035646 NM_182532 TMEM61 7901687 NM_003538 HIST1H4A 5322 8117334 AK125166 LOC441268 8141166 NM_001001521 UGP2 00040, 00052, 8052624 00500, 00520, 01100 NR_001445 RN7SK 8120249 NM_001551 IGBP1 8168087 NM_138417 KTI12 7916130 NM_031213 FAM108A1 8032371, 7904869, 7904948, 7924230 or 8074842 BC001181 FAM173A 7992043 NM_001031 RPS28 3010 8005471, 8025395 or 7942824 NM_004175 SNRPD3 03040, 05322 8071920 NM_001044370 MPPED1 8073623 BC005079 C2orf42 8052834 NM_003542 HIST1H4C 5322 8117368 BC033986 LOC440934 8048712 NM_001082575 RBFOX3 8018993 NM_017900 AURKAIP1 7911532 or 8039923 NM_001024598 HES3 7897280 NM_022061 MRPL17 7946267 NM_001029 RPS26 3010 8007797 NM_016060 MED31 8011968 NM_012394 PFDN2 7921786 NM_015965 NDUFA13 00190, 05010, 8027205 05012, 05016 NM_080603 ZSWIM1 8063074 NM_021104 RPL41 3010 7957530, 7965467, 7982129, 8105432 or 8075691 NM_000847 GSTA3 00480, 00980, 8127087 00982 NM_032753 RAX2 8032601 NM_003684 MKNK1 04010, 04910 7915846 NM_003577 UTF1 7931553 NM_022363 LHX5 7966631 NM_001037495 DYNLL1 4962 7967067 NM_004609 TCF15 8064370 AK098732 TRAP1 7992954 NM_144999 LRRC45 8010719 NM_001018138 NME2 00230, 00240, 8180388, 01100 8180389, 8180387 or 8180386 NM_002528 NTHL1 3410 7998692 NM_006087 TUBB4 04145, 04540, 8025051 05130 NM_003493 HIST3H3 5322 7924884 NR_026800 KIAA0125 7977440 NM_015456 COBRA1 8159654 NM_006088 TUBB2C 04145, 04540, 8165496 05130 NM_002307 LGALS7 8036584 or 8028546 NM_181887 UBE2D3 04120, 04141 8180330, 8180335, 8180334, 8180331, 8180333, 8180329 or 8180332 NM_001348 DAPK3 05200, 05219 8032718 NM_005319 HIST1H1C 8124397 NM_178536 LCN12 8159501 NR_003666 SPDYE7P 8133209 AK125308 LOC100129484 8137962 NM_020412 CHMP1B 4144 8020179 NM_003550 MAD1L1 04110, 04914 8137805 NM_032527 ZGPAT 8064156 NR_003051 RMRP 8161024 NR_029681 MIR140 7997008 NM_006858 TMED1 8034101 NM_006312 NCOR2 4330 7959772 AK095987 FLJ38668 8054449 ENST00000427835 C20orf61 8065013 NM_001144936 C11orf95 7949015 NM_173547 TRIM65 8018502 NM_014370 SRPK3 8170753 NM_005574 LMO2 7947450 NM_001007595 C2CD4B 7989473 NM_001168 BIRC5 05200, 05210 8018860 NM_021012 KCNJ12 8005726 NM_144589 COMTD1 7934544 NM_016589 TIMMDC1 8081867 NM_012315 KLK9 8038716 NM_006292 TSG101 4144 7947015 NM_033055 HIAT1 7903294 NM_001113201 NACA 7964262 NM_181838 UBE2D2 04120, 04141, 8108435 05131 NM_005973 PRCC 7906235 NM_005274 GNG5 4062 8174509 NM_006770 MARCO 4145 8044773 NM_014674 EDEM1 4141 8085116 NM_145657 GSX1 7968260 NM_002003 FCN1 8165011 NM_003001 SDHC 00020, 00190, 8011212 01100, 05010, 05012, 05016 NM_018942 HMX1 8104136 NM_006848 CCDC85B 7941457 NM_032338 LLPH 7956876 NM_015971 MRPS7 8009784 NM_020180 CELF4 8022952 NM_001080495 TNRC18 8137959 NM_006181 NTN3 4360 7992632 AK094921 LOC100131763 8049950 NM_198545 C1orf187 7897737 NM_002066 GML 8148565 NM_031899 GORASP1 8086317 NM_012452 TNFRSF13B 04060, 04672, 8013061 05340 NM_138574 HDGFL1 8117172 NM_024816 RABEP2 8000616 NM_022097 CHP2 04010, 04020, 7994123 04114, 04210, 04310, 04360, 04370, 04650, 04660, 04662, 04720, 05010, 05014 NM_006801 KDELR1 5110 8038078 NM_004939 DDX1 8040386 NM_130784 SYCE1 7937247 NM_019082 DDX56 8139392 NM_001039916 ZNF384 7953390 NM_016602 CCR10 04060, 04062, 8015681 04672 NR_024591 POM121L1P 8074714 NM_020064 BARHL1 8158912 NM_006356 ATP5H 00190, 01100, 8018288 05010, 05012, 05016 NM_012249 RHOQ 4910 8041808 NR_002951 SNORA2B 7962829 NR_004430 RNU1-1 7919269, 7919349, 7898375, 7898411, 7912800, 7912850, 7919576, 7973896 or 7978568 NM_001126128 PROK2 8088813 NM_016063 HDDC2 8129363 NM_005706 TSSC4 7937813 NR_002781 TSPY26P 8065603 NM_175064 SPDYE1 8140424 or 8140454 NM_138350 THAP3 7897329 AY730278 CENPVL1 8167652 or 8172715 NM_002669 PLRG1 3040 8103289 NM_006476 ATP5L 00190, 01100 7944216 NM_031909 C1QTNF4 7947928 NM_032805 ZSCAN10 7998921 NM_001804 CDX1 8109226 NM_014976 PDCD11 7936096 AK097604 LOC100130285 7998265 NM_003168 SUPT4H1 8016982 NM_016835 MAPT 04010, 05010 8016263 NM_001002 RPLP0 3010 8109750 NM_016305 SS18L2 8079074 NM_001033113 ENTPD8 00230, 00240 8165538 NM_003926 MBD3 8032275 NM_031280 MRPS15 7914940 NR_026676 RPS2P32 8131869 NM_145803 TRAF6 04010, 04120, 7947540 04144, 04380, 04620, 04621, 04622, 04722, 05140, 05142, 05145, 05160, 05200, 05222 NM_000858 GUK1 00230, 01100 7910241 NM_139172 TMEM190 8031475 NM_018047 RBM22 3040 8115168 NM_182702 PRSS42 8086683 NM_003859 DPM1 00510, 01100 8067017 NM_003002 SDHD 00020, 00190, 7943853 or 01100, 05010, 7899016 05012, 05016 NR_026716 KIR3DX1 8031200 NM_015719 COL5A3 04510, 04512, 8033825 04974, 05146 L20860 SEPT5-GP1BB 8071272 NM_101395 DYRK1A 8068551 NM_014419 DKKL1 8030292 NR_026557 PLK5 8024331 BC043386 C19orf68 8029996 NM_001080440 OTOL1 8083770 NM_144578 MAPK1IP1L 7974455 NM_012145 DTYMK 00240, 01100 8060286 or 8077262 NM_002804 PSMC3 3050 7947867 NM_001172743 RAO 8171539 NM_016547 SDF4 7911422 NM_175741 C15orf55 7982516 NM_003910 BUD31 3040 8134589 NM_014342 MTCH2 7947934 NM_001013 RPS9 3010 8180398 or 8031152 NM_021646 ZNF500 7999196 AY341951 FAM138D 7960172 NM_005034 POLR2K 00230, 00240, 8147654 01100, 03020, 05016 NM_001005922 KRTAP5-1 7945645 NM_001105669 TTC24 7906177 NM_006043 HS3ST2  534 7994052 NM_173641 EPHA10 7915078 NM_001010908 C1QL3 7932308 NM_001164094 COPS7A 7953395 NM_014582 OBP2A 8180231 NM_024319 C1orf35 7924842 NM_003375 VDAC2 04020, 05012, 8042335 05016 NM_007374 SIX6 7974793 NM_001003684 UQCR10 00190, 01100, 8072274 04260, 05010, 05012, 05016 NR_000025 SNORD15B 7942594 AF304442 C21orf118 8068046 NM_016312 WBP11 3040 7961489 NM_080875 MIB2 7896985 NM_005922 MAP3K4 04010, 04912 8130624 NR_002576 SNORA21 8014755 NM_018462 BRK1 4810 8085287 NR_003013 SCARNA16 8010137 NM_005609 PYGM 00500, 04910 7949124 NM_016438 HIGD1B 8007701 NM_004855 PIGB 00563, 01100 7983811 NR_026713 FAM182A 8065527 NM_003537 HIST1H3B 5322 8124388 NM_001040436 YARS2  970 7962203 NM_014171 CRIPT 8041813 NM_053056 CCND1 04110, 04115, 7950012 04310, 04510, 04630, 05200, 05210, 05212, 05213, 05214, 05215, 05216, 05218, 05219, 05220, 05221, 05222, 05223, 05416 AF067420 IGHA1 7995263 NM_198180 QRFP 8164630 BC004224 SHANK2-AS3 7942228 NM_019107 C19orf10 8032863 NM_001800 CDKN2D 4110 8034075 NM_014860 SUPT7L 8051204 NM_000183 HADHB 00062, 00071, 8040639 00280, 01100 NM_001258 CDK3 8010021 NM_005247 FGF3 04010, 04810, 7950036 05200, 05218 NM_007255 B4GALT7 00532, 00534, 8110399 01100 NM_016199 LSM7 03018, 03040 8032480 BC004943 MGC10814 8035551 NR_024593 POM121L10P 8075024 NM_145719 TIGD3 7941255 NM_001164440 ANKRD33B 8104499 NM_174923 CCDC107 8155073 NM_015276 USP22 8013486 NM_001164447 FAM90A10 8144448 NM_133261 GIPC3 8024676 NM_001037984 SLC38A10 8019149 NM_006855 KDELR3 5110 8073015 NM_021944 C14orf93 7977868 NM_005430 WNT1 04310, 04340, 7955170 04916, 05200, 05217 NM_199044 NSUN4 7901219 AK125575 ZNF425 8143708 NM_032344 NUDT22 7940884 NM_018090 NECAP2 7898337 NM_000377 WAS 04062, 04520, 8167334 04666, 04810, 05100, 05130, 05131 NM_001001410 C16orf42 7998449 NM_148172 PEMT 00564, 01100 8013120 NM_001032363 C1orf151 7898574 NM_002949 MRPL12 8010664 NM_012094 PRDX5 4146 7940996 NR_001555 GOLGA2P2Y 8176910 or 8177413 NM_025072 PTGES2 00590, 01100 8164362 NM_138983 OLIG1 8068235 NM_016568 RXFP3 8104781 NM_152914 C17orf103 8013509 NM_014170 GTPBP8 8081676 NM_003513 HIST1H2AB 5322 8124391 NM_003278 CLEC3B 8079305 NM_004637 RAB7A 04144, 04145, 8082431 05146 NM_001144954 C5orf47 8110068 NM_001048183 PHACTR4 7899455 NM_004551 NDUFS3 00190, 01100, 7939825 05010, 05012, 05016 NM_006808 SEC61B 03060, 04141, 8156838 04145, 05110 NM_020199 C5orf15 8114138 NM_030811 MRPS26 8060599 NR_026581 MLF2 7960689 NM_002297 LCN1 8159255 BC104424 FAHD2B 8043682 NM_005714 KCNK7 7949444 NM_001099435 SPDYE5 8133654 BC035374 TCEANC2 7901592 NM_005091 PGLYRP1 8037742 NM_001013653 LRRC26 8165453 NM_182498 ZNF428 8037355 NM_001024678 LRRC24 8153868 NM_001114600 C1orf144 7898328 NM_001614 ACTG1 04145, 04510, 8019183 04520, 04530, 04670, 04810, 05100, 05110, 05130, 05131, 05410, 05412, 05414, 05416 NM_000383 AIRE 04120, 05340 8069037 NR_002911 SNORA71A 8066258 NM_001135580 C19orf71 8024655 NM_145272 C17orf50 8006569 NM_000154 GALK1 00052, 00520, 8018428 01100 AY358234 LOC100129831 8024444 NM_001100418 C19orf60 8027032 NM_020996 FGF6 04010, 04810, 7960407 05200, 05218 NM_001297 CNGB1 04740 04744 8001615 AK128227 LOC100130236 7919299 or 7919380 NM_002494 NDUFC1 00190, 01100, 8102839 05010, 05012, 05016 NM_198175 NME1 00230, 00240, 8008517 01100 NM_000479 AMH 04060, 04350 8024429 NM_001145250 SP9 8056825 NR_002144 LOC407835 8136065 NM_014110 PPP1R8 7914139 NM_152898 FERD3L 8138450 NR_030170 MIR202 7937148 NM_177398 LMX1A 7921936 NM_178348 LCE1A 7905528 NM_005444 RQCD1 3018 8048340 NM_173806 PDZD9 8000229 NM_006857 SNRNP27 3040 8042495 NM_033644 FBXW11 04114, 04120, 8115765 04310, 04340, 04710, 05131 NM_001164456 FAM90A13 8149204, 8144428, 8144432, 8144436 or 8144444 NM_020070 IGLL1 5340 8074909 NM_005007 NFKBIL1 8118127, 8177967 or 8179249 NM_177542 SNRPD2 3040 8037642 NM_020637 FGF22 04010, 04810, 8023990 05200, 05218 NM_144727 CRYGN 8143949 NM_015568 PPP1R16B 8062557 NM_018250 INTS9 8150014 NM_003517 HIST2H2AC 5322 7905088 NM_032998 DEDD 7921793 NM_173660 DOK7 8093807 NM_015679 TRUB2 8164428 NM_030657 LIM2 8038815 NM_015918 POP5 03008, 03013 7967084 NR_029833 MIR30C1 7900490 NM_001004 RPLP2 3010 7937476 NM_152778 MFSD8 4142 8102730 NM_032595 PPP1R9B 8016628 NM_006686 ACTL7B 8163019 AK291454 UBE2K 4120 8099918 NM_000983 RPL22 3010 7911989 NM_053049 UCN3 7925950 NM_001030047 KLK3 05200, 05215 8030753 NR_003502 ZNRF2P1 8132209 NM_016734 PAX5 8161211 NM_052945 TNFRSF13C 04060, 04672, 8076387 05340 NM_006299 ZNF193 8117655 NM_002764 PRPS1 00030, 00230, 8169240 01100 NM_001024675 C20orf134 8061944 NM_014064 METTL11A 8158544 NM_001002252 ARL6IP4 7959549 NM_004640 DDX39B 03013, 03015, 8178476, 03040 8179750 or 8124926 NM_173514 SLC38A9 8112121 NM_018955 UBB 5012 8005166 NM_001130861 CLDN5 04514, 04530, 8074473 04670, 05160 NM_006432 NPC2 4142 7980146 AB016902 HGC6.3 8130824 NM_000413 HSD17B1 00140, 01100 8007263 NM_001142467 HES4 7911376 NM_181802 UBE2C 4120 8063043 NM_001164453 FAM90A20 8144388 NM_178548 TFAP2E 7900001 NM_032810 ATAD1 7934870 NM_001003682 TMEM200B 7914232 NM_003013 SFRP2 4310 8103254 NM_033178 DUX4 8098732, 8098740, 8098725, 8104122, 8098730, 8098743 or 7931665 NM_003110 SP2 8008052 NM_021570 BARX1 8162472 NR_002798 NAPSB 8038547 NM_001029865 DBX1 7947129 NM_178138 LHX3 8165083 NM_005202 COL8A2 7914880 NM_001069 TUBB2A 04145, 04540, 8116649 or 05130 8116653 NM_006943 SOX12 8060334 NR_029485 MIR15A 7971661 NM_000986 RPL24 3010 8126450 NM_018158 SLC4A1AP 8041015 NM_012188 FOXI1 8109901 NM_031917 ANGPTL6 8033892 NM_006118 HAX1 7905733 NM_000290 PGAM2 00010, 01100 8139276 NM_024888 LPPR3 8032094 NM_002477 MYL5 04510, 04530, 8093386 04670, 04810 NM_138383 MTSS1L 7997135 NM_004435 ENDOG 4210 8158418 BC008667 PANK2 00770, 01100 8060736 NM_174920 SAMD14 8016615 NM_014581 OBP2B 8180358 NM_176677 NHLRC4 7991898 NM_031157 HNRNPA1 3040 7955890 NR_024420 LOC389634 7960894 NM_032574 DPY30 8051387 NM_138705 CALML6 04020, 04070, 7897026 04114, 04270, 04720, 04722, 04740, 04744, 04910, 04912, 04916, 04970, 04971, 05010, 05214 BC036197 MGC39545 7944972 BC036837 C20orf201 8067812 NM_001111322 DDX54 7958948 NM_016219 MAN1B1 00510, 01100, 8159566 04141 NR_029618 MIR199A2 7922328 NM_001113324 TEN1 8010017 NM_015414 RPL36 3010 8024966 NM_014183 DYNLRB1 8062016 NM_004781 VAMP3 04130, 04145 7897370 NM_002714 PPP1R10 8124756, 8178358 or 8179664 NM_020341 PAK7 04012, 04360, 8064952 04510, 04660, 04810, 05211 NM_080625 C20orf160 8061653 NM_003969 UBE2M 4120 8039805 NM_006232 POLR2H 00230, 00240, 8084488 01100, 03020, 05016 NM_002900 RBP3 7933359 NM_025147 COQ10B 8047217 NM_016932 SIX2 8051949 NM_012210 TRIM32 4120 8157516 NM_019612 IRGC 8029318 NM_013234 EIF3K 8028514 NM_178351 LCE1C 7920193 NM_007167 ZMYM6 7914764 NM_004278 PIGL 00563, 01100 8005157 NM_014688 USP6NL 7926150 NM_006563 KLF1 8034578 NM_207305 FOXD4 8159808 NM_001012710 KRTAP5-10 7942267 NM_020415 RETN 8025278 NM_005225 E2F1 04110, 05200, 8065710 05212, 05214, 05215, 05218, 05219, 05220, 05222, 05223 NM_020839 WDR48 8078834 NM_003332 TYROBP 04380, 04650 8036224 NM_003396 WNT9B 04310, 04340, 8007895 04916, 05200, 05217 NR_026811 AGSK1 7985571 NM_024095 ASB8 7962783 NM_001330 CTF1 04060, 04630 7994961 NM_080865 GPR62 8080158 NM_144582 TEX261 8042566 NM_032328 EFCAB2 7925585 NM_032772 ZNF503 7928529 NM_000194 HPRT1 00230, 00983, 8169984 01100 NM_001009606 HS3ST6 7998634 NM_001100119 XRCC3 3440 7981447 NR_029703 MIR150 8038393 NM_057176 BSND 7901691 NR_003008 SCARNA5 8049297 NM_015913 TXNDC12  480 7916120 NM_006612 KIF1C 8004057 NM_002798 PSMB6 3050 8003953 NM_000684 ADRB1 04020, 04080, 7930627 04144, 04540, 04970, 05414 NM_024812 BAALC 8147756 NM_175078 KRT77 7963502 NM_144736 C2orf56 8041495 NM_002460 IRF4 8116559 NM_001001520 HDGFRP2 8024864 NM_001168479 ARMCX5 8168958 NR_029596 MIR129-1 8135907 NM_005565 LCP2 04380, 04650, 8115734 04660, 04664 NM_001099279 FOXD4L2 8161571, 8155440 or 8161583 NM_198595 AFAP1 8094030 NM_002676 PMM1 00051, 00520, 8076355 01100 NR_003594 REXO1L2P 8151603, 8151607, 8151623, 8151619 or 8151627 NM_006427 SIVA1 7977288 NM_032152 PRAM1 8033587 NM_001144995 CCDC85C 7981273 NR_002449 SNORA65 8164215 NM_001002909 GPATCH8 8016077 NM_016558 SCAND1 8066031 NM_024335 IRX6 7995674 NM_004788 UBE4A 4120 7944195 NM_021247 PRM3 7999431 NR_024368 FLJ45340 7945344 AK093358 FAM27A 8161442 NM_033467 MMEL1 7911767 NR_002937 C14orf19 7973900 NM_182973 TMPRSS9 8024467 NM_018663 PXMP2 4146 7967789 NM_173728 ARHGEF15 8004842 NM_004610 TCP10 8123374 NM_006013 RPL10 3010 8034416 or 8109821 NM_015999 ADIPOR1 4920 7923503 NM_020209 SHD 8024808 NR_029829 MIR194-2 7949275 NM_198998 AQP12A 8060126 NM_002233 KCNA4 7947270 NM_022098 XPNPEP3 8073311 NM_212550 BLOC1S3 8029640 NM_198949 NUDT1 8131101 NM_006626 ZBTB6 8163999 NM_003795 SNX3 8128683 NR_029663 MIR15B 8083737 NM_207397 CD164L2 7914084 NM_014280 DNAJC8 7899422 NM_001001915 OR2G2 4740 7911207 NM_004930 CAPZB 7913169 NM_015950 MRPL2 8126512 NM_015509 NECAP1 7953715 NM_006894 FMO3  982 7907249 NM_012483 GNLY 8043236 NM_001004333 RNASEK 8004237 NM_147196 TMIE 8079426 NR_027850 MTX2 8046573 NM_001037283 EIF3B 3013 8131111 NM_178463 C20orf166 8063914 BC090923 C17orf90 8019238 NM_020825 CRAMP1L 7992302 NM_001080520 DRGX 7933501 NM_153232 EID2 8036749 NM_012186 FOXE3 7901309 NM_213605 ZNF517 8148932 NM_178456 C20orf85 8063601 NM_032547 SCOC 8097521 NM_001170738 IQSEC3 4144 8067820 NM_024591 CHMP6 4144 8010550 NM_014515 CNOT2 3018 7957106 NM_138387 G6PC3 8007561 NM_024326 FBXL15 7930099 NM_007262 PARK7 5012 7897404 NR_001527 TTTY6 8176782 or 8177347 NM_001142588 NFYC 4612 7915345 NM_001080489 GLOD5 8167356 NM_199243 GPR150 8106976 NM_000729 CCK 8086391 NM_024718 C9orf86 8159415 NM_145729 MRPL24 7921121 NM_030662 MAP2K2 04010, 04012, 8032761 04270, 04370, 04540, 04620, 04650, 04660, 04662, 04664, 04720, 04722, 04730, 04810, 04910, 04912, 04916, 05020, 05200, 05211, 05213, 05214, 05215, 05216, 05218, 05219, 05220, 05221, 05223 NM_058190 FAM207A 8180370 NM_001011 RPS7 3010 8005877 NM_014336 AIPL1 8011912 NM_178354 LCE1F 7905517 NM_005470 ABI1 7932616 NM_006357 UBE2E3 04120, 04141 8166124 NR_002182 NACAP1 8147693 NM_001109763 GSG1L 8000467 NM_001085365 MZT2A 8055287 NM_001080468 SYCN 8036699 NM_003365 UQCRC1 00190, 01100, 8087100 04260, 05010, 05012, 05016 NM_153207 AEBP2 7954279 NM_032477 MRPL41 8159687 NM_152911 PAOX 4146 7931582 NM_002488 NDUFA2 00190, 01100, 8114618 05010, 05012, 05016 NM_175895 C12orf61 7964642 NM_004558 NRTN 8024995 NM_198850 PHLDB3 8037315 NR_023343 RNU4ATAC 8044961 NM_004976 KCNC1 7938738 NM_012184 FOXD4L1 8044634 NM_054028 SLC35G5 8020162 NM_006985 NPIP 7999766 NM_138334 JOSD2 8038571 NM_014613 FAF2 8110169 NM_022466 IKZF5 7936826 NM_022731 NUCKS1 7909142 NM_138284 IL17D 7967969 NM_004851 NAPSA 4142 8038556 NM_031292 PUS7L 7962427 NM_017871 CPSF3L 7911486 NM_012476 VAX2 8042532 NM_032343 CHCHD6 8082305 NM_199287 CCDC137 8010629 BC043417 TMEM68 8146480 NR_029714 MIR320A 8149705 NM_207163 LMOD2 8135821 NM_024339 THOC6 3013 7992795 NM_032411 C2orf40 8044143 NM_016491 MRPL37 7901601 NM_003089 SNRNP70 3040 8030199 NM_014360 NKX2-8 7978686 NM_201589 MAFA 04930, 04950 8153409 AK289373 IGHG1 8001104 NM_005583 LYL1 8034608 NM_022375 OCLM 7908347 NM_001006610 SIAH1 04115, 04120, 8001306 04310 NM_172229 KREMEN2 7992758 NM_021996 GBGT1 00603, 01100 8164833 NM_194249 DND1 8114625 NM_001142864 PIEZO1 7997827 NM_178438 LCE5A 7905483 NM_001349 DARS  970 8055445 NM_176806 MOCS2 4122 8112020 NR_024355 BK250D10.8 8073546 NM_024768 CCDC48 8082465 AK093505 SPANXA2-OT1 8175537 NM_024754 PTCD2 8106107 AK125905 LOC100129581 8050113 NM_175619 ZAR1 8094968 NM_001867 COX7C 00190, 01100, 8106776 04260, 05010, 05012, 05016 NM_031492 RBM4B 7949674 NM_153376 CCDC96 8099242 NM_002034 FUT5 00601, 01100 8033064 NM_181462 MRPL55 7924853 NM_012257 HBP1 8135392 NR_027780 HMGXB4 8072645 NM_004822 NTN1 4360 8004880 NM_178454 DRAM2 7918474 NM_015893 PRLH 8049509 NM_024313 NOL12 8072883 NM_006522 WNT6 04310, 04340, 8048445 04916, 05200, 05217 NM_017832 FAM206A 8157144 NM_006947 SRP72 3060 8095230 NM_021948 BCAN 7906205 NM_001164405 BHLHA9 8003633 NM_032830 CIRH1A 3008 7996891 NM_080680 COL11A2 04510, 04512, 8125568 04974, 05146 NM_002622 PFDN1 8114567 NM_002196 INSM1 8061303 NM_002370 MAGOH 03013, 03015, 7916274 03040 NR_024406 LOC732275 8003230 NM_201653 CHIA  520 7903945 AK296222 LOC728093 8112476 NM_004343 CALR 04141, 04145, 8026106 04612, 05142 NM_001003892 DUPD1 7934527 NR_026837 LOC283392 7964976 NM_006274 CCL19 04060, 04062 8160879 NM_014847 UBAP2L 7905700 NM_016396 CTDSPL2 7983335 NM_015944 AMDHD2  520 7992656 NM_144567 ANGEL2 7924190 NM_153270 KLHL34 8171786 NM_080622 ABHD16B 8064203 NM_022753 S100PBP 7899829 AK290103 LOC100287934 7909990 NR_000011 SNORA70 8170863 NM_003968 UBA3 4120 8088718 NM_033257 DGCR6L 8074565 NM_016468 COX16 7979906 NM_030642 APOL5 8072721 NM_002565 P2RY4 4080 8173366 NM_014017 LAMTOR2 7906072 NM_006192 PAX1 8061357 NM_133450 ANKS3 7999177 NM_024302 MMP28 8014282 NM_016166 PIAS1 04120, 04630, 7984453 05160, 05200, 05222 NM_007037 ADAMTS8 7952752 NR_033192 CCDC59 7965200 NM_174895 PCP2 8033414 NM_003279 TNNC2 4020 8066590 NM_001136262 ATXN7L3B 7957242 NM_004108 FCN2 8159211 NM_032829 C12orf34 7958577 NM_139136 KCNC2 7964987 NM_033113 ZNF628 8031489 NM_005687 FARSB  970 8059319 NM_000180 GUCY2D 00230, 04740, 8004763 04744 NM_024309 TNIP2 8099029 NM_014554 SENP1 7962760 NM_001013735 FOXB2 8155942 NM_174922 ADCK5 8148850 NM_032704 TUBA1C 04145, 04540, 7955179 05130 NM_020385 REXO4 8164907 NR_029894 MIR148B 7955906 NM_001040425 U2AF1L4 8036143 NR_029945 MIR423 8006119 U63828 C20orf181 8067754 NM_133636 HELQ 8101467 NM_001102614 SLC35G6 8004428 NM_004549 NDUFC2 00190, 01100, 7950644 05010, 05012, 05016 AY358101 DBF4B 8007673 NM_032842 TMEM209 8142912 NM_001862 COX5B 00190, 01100, 8043718 04260, 05010, 05012, 05016 NM_020535 KIR2DL5A 04612, 04650, 8039884 05332

In another embodiment, cycling hypoxia markers are selected from the list of the 298 cycling hypoxia markers of Table 3 below, as well as their variants, fragments or equivalents. Table 3 comprises cycling hypoxia markers identified in the conditions of the Example and presenting an average FDR corrected p-value over 200 data resampling lower than 0.05.

TABLE 3 GeneBank Name of the Accession Number marker Pathways Probeset NR_002312 RPPH1 7977507 BC018448 MALAT1 7949410 AF284753 UIMC1 8165703, or 7911343 NM_014248 RBX1 03420, 04110, 8073334 04114, 04120, 04141, 04310, 04350, 04710, 05200, 05211 NR_003287 RN28S1 7942875 NM_177987 TUBB8 04145, 04540, 7911355 05130 NM_170601 SIAE 7944867 NM_001012708 KRTAP5-3 7945652 NR_029710 MIR193A 8006321 NM_000981 RPL19 3010 8006845 NM_003792 EDF1 8165309 NM_012217 TPSD1 7992191 NR_029824 MIR128-2 8078527 NM_003731 SSNA1 8159609 BC013044 DNAJA2 4141 7995379 NM_001037160 CYS1 8050232 NM_004352 CBLN1 8001329 NM_006160 NEUROD2 8014865 NM_001017 RPS13 3010 7946812 NM_017854 TMEM160 8037853 NM_152568 NKX6-3 8150433 NM_001417 EIF4B 03013, 04150 7963575 NM_003094 SNRPE 3040 8160033 NR_002715 RN7SL1 8040338 NM_016170 TLX2 8042896 NM_000307 POU3F4 8168567 NM_016057 COPZ1 7955896 NM_012322 LSM5 03018, 03040 8138912 AK302042 LOC440518 8027343 NM_000863 HTR1B 4080 8127692 NM_003512 HIST1H2AC 5322 8117372 NM_001080113 C14orf184 7980859 NR_024583 POM121L8P 8071168 NM_145232 CTU1 4122 8038782 AK123383 LOC642648 8076747 NM_032479 MRPL36 8110861 NM_007241 SNF8 4144 8016508 NM_016564 CEND1 7945536 NR_033335 SNORA70G 7964830 NM_144615 TMIGD2 8032782 NM_003538 HIST1H4A 5322 8117334 NM_016424 LUC7L3 8016733 NM_032231 FAM96A 7989611 NM_014206 C11orf10 7948606 NR_000009 SNORD4B 8005957 NM_001135086 PRSS41 7992716 AK125166 LOC441268 8141166 NR_001445 RN7SK 8120249 NM_001551 IGBP1 8168087 NM_005608 PTPRCAP 7949792 NM_145203 CSNK1A1L 04310, 04340 7971071 NM_023002 HAPLN4 8035646 NM_003542 HIST1H4C 5322 8117368 NM_001001521 UGP2 00040, 00052, 8052624 00500, 00520, 01100 NM_031210 SLIRP 7975989 NM_013299 SAC3D1 7941122 NM_001044370 MPPED1 8073623 NM_004175 SNRPD3 03040, 05322 8071920 NM_006327 TIMM23 7927548 NM_031213 FAM108A1 8032371 NM_001031 RPS28 3010 8025395, 8005471, or 7942824 BC033986 LOC440934 8048712 BC005079 C2orf42 8052834 BC001181 FAM173A 7992043 NM_000847 GSTA3 00480, 00980, 8127087 00982 NM_017900 AURKAIP1 8039923 or 7911532 NM_001018138 NM_E2 00230, 00240, 8180388, 01100 8180389, 8180387 or 8180386 NM_001082575 RBFOX3 8018993 NM_015456 COBRA1 8159654 NM_080603 ZSWIM1 8063074 NM_001029 RPS26 3010 8007797 NM_006088 TUBB2C 04145, 04540, 8165496 05130 NM_004609 TCF15 8064370 NM_181887 UBE2D3 04120, 04141 8180330, 8180335, 8180331, 8180334, 8180333, 8180329 or 8180332 NM_015965 NDUFA13 00190, 05010, 8027205 05012, 05016 NM_178536 LCN12 8159501 NM_032753 RAX2 8032601 NM_016060 MED31 8011968 NR_003666 SPDYE7P 8133209 AK125308 LOC100129484 8137962 NR_003051 RMRP 8161024 NM_005319 HIST1H1C 8124397 NM_003550 MAD1L1 04110, 04914 8137805 ENST00000427835 C20orf61 8065013 NM_144999 LRRC45 8010719 NM_006087 TUBB4 04145, 04540, 8025051 05130 NR_029583 MIR197 7903717 NM_002307 LGALS7 8036584 or 8028546 NM_014370 SRPK3 8170753 AK098732 TRAP1 7992954 NM_001348 DAPK3 05200, 05219 8032718 NM_022061 MRPL17 7946267 NM_002528 NTHL1 3410 7998692 NM_032527 ZGPAT 8064156 NM_006858 TMED1 8034101 NM_005274 GNG5 4062 8174509 NM_022363 LHX5 7966631 NM_001037495 DYNLL1 4962 7967067 NM_021104 RPL41 3010 7957530 AK095987 FLJ38668 8054449 NM_181838 UBE2D2 04120, 04141, 8108435 05131 NM_002003 FCN1 8165011 NM_016589 TIMMDC1 8081867 NM_020412 CHMP1B 4144 8020179 NR_026800 KIAA0125 7977440 NM_014674 EDEM1 4141 8085116 NM_138417 KTI12 7916130 NM_012315 KLK9 8038716 NR_029681 MIR140 7997008 NM_173547 TRIM65 8018502 NM_003577 UTF1 7931553 NM_138574 HDGFL1 8117172 NM_018942 HMX1 8104136 NM_001080495 TNRC18 8137959 NM_002066 GML 8148565 NM_001168 BIRC5 05200, 05210 8018860 NM_020064 BARHL1 8158912 NM_021012 KCNJ12 8005726 NM_001007595 C2CD4B 7989473 NM_031899 GORASP1 8086317 NM_019082 DDX56 8139392 AY730278 CENPVL1 8172715 or 8167652 NM_175064 SPDYE1 8140424 or 8140454 NM_001033113 ENTPD8 00230, 00240 8165538 NM_006770 MARCO 4145 8044773 AK094921 LOC100131763 8049950 NM_001126128 PROK2 8088813 NM_016063 HDDC2 8129363 NM_182532 TMEM61 7901687 NR_024591 POM121L1P 8074714 NM_020180 CELF4 8022952 NM_012394 PFDN2 7921786 NM_006312 NCOR2 4330 7959772 NM_001804 CDX1 8109226 NR_026676 RPS2P32 8131869 NM_001002 RPLP0 3010 8109750 NR_002781 TSPY26P 8065603 NM_003001 SDHC 00020, 00190, 8011212 01100, 05010, 05012, 05016 NM_002669 PLRG1 3040 8103289 NM_006801 KDELR1 5110 8038078 NM_015971 MRPS7 8009784 NM_003684 MKNK1 04010, 04910 7915846 NM_018047 RBM22 3040 8115168 NM_012249 RHOQ 4910 8041808 NM_001172743 RAI2 8171539 NM_016305 SS18L2 8079074 NM_001113201 NACA 7964262 NM_001144936 C11orf95 7949015 NM_012452 TNFRSF13B 04060, 04672, 8013061 05340 NM_004939 DDX1 8040386 NM_003493 HIST3H3 5322 7924884 NM_001013 RPS9 3010 8180398 NM_006356 ATP5H 00190, 01100, 8018288 05010, 05012, 05016 NM_145657 GSX1 7968260 NM_182702 PRSS42 8086683 NM_005574 LMO2 7947450 NM_003926 MBD3 8032275 NM_024816 RABEP2 8000616 NM_003859 DPM1 00510, 01100 8067017 NM_022097 CHP2 04010, 04020, 7994123 04114, 04210, 04310, 04360, 04370, 04650, 04660, 04662, 04720, 05010, 05014 NM_014582 OBP2A 8180231 L20860 SEPT5-GP1BB 8071272 NM_016602 CCR10 04060, 04062, 8015681 04672 NM_006292 TSG101 4144 7947015 NM_003910 BUD31 3040 8134589 NM_005034 POLR2K 00230, 00240, 8147654 01100, 03020, 05016 NM_032338 LLPH 7956876 NM_003168 SUPT4H1 8016982 NM_006181 NTN3 4360 7992632 NM_012145 DTYMK 00240, 01100 8077262 or 8060286 NM_032805 ZSCAN10 7998921 NR_026716 KIR3DX1 8031200 NM_016835 MAPT 04010, 05010 8016263 NM_001080440 OTOL1 8083770 NM_198180 QRFP 8164630 NM_139172 TMEM190 8031475 NM_101395 DYRK1A 8068551 NM_003537 HIST1H3B 5322 8124388 BC043386 C19orf68 8029996 NM_144589 COMTD1 7934544 NM_005922 MAP3K4 04010, 04912 8130624 NM_018462 BRK1 4810 8085287 AK097604 LOC100130285 7998265 NM_015719 COL5A3 04510, 04512, 8033825 04974, 05146 NR_002951 SNORA2B 7962829 NM_001039916 ZNF384 7953390 AF304442 C21orf118 8068046 NR_026557 PLK5 8024331 NM_000377 WAS 04062, 04520, 8167334 04666, 04810, 05100, 05130, 05131 NM_006848 CCDC85B 7941457 NR_001555 GOLGA2P2Y 8177413 or 8176910 NM_001003684 UQCR10 00190, 01100, 8072274 04260, 05010, 05012, 05016 NM_174923 CCDC107 8155073 NM_014419 DKKL1 8030292 NM_025072 PTGES2 00590, 01100 8164362 NM_001164447 FAM90A10 8144448 AK125575 ZNF425 8143708 NM_006808 SEC61B 03060, 04141, 8156838 04145, 05110 NM_007255 B4GALT7 00532, 00534, 8110399 01100 NM_001164440 ANKRD33B 8104499 NM_021646 ZNF500 7999196 NM_031909 C1QTNF4 7947928 NM_002297 LCN1 8159255 NM_001013653 LRRC26 8165453 NM_014171 CRIPT 8041813 NM_003375 VDAC2 04020, 05012, 8042335 05016 NM_003513 HIST1H2AB 5322 8124391 NM_001024678 LRRC24 8153868 NR_024593 POM121L10P 8075024 NR_026713 FAM182A 8065527 NM_001144954 C5orf47 8110068 NM_001099435 SPDYE5 8133654 NM_175741 C15orf55 7982516 NM_020199 C5orf15 8114138 NM_000183 HADHB 00062, 00071, 8040639 00280, 01100 NM_014860 SUPT7L 8051204 NM_016568 RXFP3 8104781 NM_014976 PDCD11 7936096 NR_002576 SNORA21 8014755 NM_144578 MAPK1IP1L 7974455 NM_006476 ATP5L 00190, 01100 7944216 NM_130784 SYCE1 7937247 NM_006043 HS3ST2  534 7994052 NR_002144 LOC407835 8136065 NM_001800 CDKN2D 4110 8034075 NM_005007 NFKBIL1 8179249, 8177967 or 8118127 NM_003278 CLEC3B 8079305 NM_002494 NDUFC1 00190, 01100, 8102839 05010, 05012, 05016 NM_006855 KDELR3 5110 8073015 BC004943 MGC10814 8035551 NM_019107 C19orf10 8032863 NM_145803 TRAF6 04010, 04120, 7947540 04144, 04380, 04620, 04621, 04622, 04722, 05140, 05142, 05145, 05160, 05200, 05222 NR_003013 SCARNA16 8010137 NM_014170 GTPBP8 8081676 NM_016438 HIGD1B 8007701 NM_016199 LSM7 03018, 03040 8032480 NM_004637 RAB7A 04144, 04145, 8082431 05146 NM_015679 TRUB2 8164428 NM_138983 OLIG1 8068235 NM_005706 TSSC4 7937813 NM_003002 SDHD 00020, 00190, 7943853 01100, 05010, 05012, 05016 NM_016734 PAX5 8161211 NM_001164456 FAM90A13 8149204 NM_014064 METTL11A 8158544 NM_006686 ACTL7B 8163019 NM_001258 CDK3 8010021 NM_030811 MRPS26 8060599 NM_133261 GIPC3 8024676 AF067420 IGHA1 7995263 NM_002764 PRPS1 00030, 00230, 8169240 01100 NM_152898 FERD3L 8138450 NM_015276 USP22 8013486 NM_144727 CRYGN 8143949 NM_001037984 SLC38A10 8019149 NM_002804 PSMC3 3050 7947867 NM_018250 INTS9 8150014 NM_033644 FBXW11 04114, 04120, 8115765 04310, 04340, 04710, 05131 NM_021570 BARX1 8162472 NM_007374 SIX6 7974793 NR_003502 ZNRF2P1 8132209 AY341951 FAM138D 7960172 NM_004640 DDX39B 03013, 03015, 8178476 or 03040 8179750 BC104424 FAHD2B 8043682 NM_000383 AIRE 04120, 05340 8069037 NM_001164453 FAM90A20 8144388 NM_004855 PIGB 00563, 01100 7983811 NM_001145250 SP9 8056825 NM_178138 LHX3 8165083 NM_152914 C17orf103 8013509 NM_173660 DOK7 8093807 NM_006299 ZNF193 8117655 NM_182498 ZNF428 8037355 NM_148172 PEMT 00564, 01100 8013120 AB016902 HGC6.3 8130824 NM_002949 MRPL12 8010664 NR_002911 SNORA71A 8066258 NM_005091 PGLYRP1 8037742 AK291454 UBE2K 4120 8099918 NM_016312 WBP11 3040 7961489 NM_004435 ENDOG 4210 8158418 NM_173514 SLC38A9 8112121 NM_014342 MTCH2 7947934 NM_152778 MFSD8 4142 8102730 NR_004430 RNU1-1 7919349 or 7919269 NM_001135580 C19orf71 8024655 NM_014581 OBP2B 8180358 NM_000479 AMH 04060, 04350 8024429 NM_001164094 COPS7A 7953395 NM_001001410 C16orf42 7998449 NM_001005922 KRTAP5-1 7945645 NM_003013 SFRP2 4310 8103254 NM_052945 TNFRSF13C 04060, 04672, 8076387 05340 NM_000290 PGAM2 00010, 01100 8139276 NM_001100418 C19orf60 8027032 NM_002714 PPP1R10 8179664 or 8178358 NM_015568 PPP1R16B 8062557 NM_020070 IGLL1 5340 8074909 NM_012188 FOXI1 8109901

In another embodiment, cycling hypoxia markers are selected from the list of the 167 cycling hypoxia markers of Table 4 below, as well as their variants, fragments or equivalents. Table 4 comprises cycling hypoxia markers identified in the conditions of the Example and presenting an average FDR corrected p-value over 200 data resampling lower than 0.01.

TABLE 4 GeneBank Name of the Accession Number marker Pathways Probeset NR_002312 RPPH1 7977507 BC018448 MALAT1 7949410 AF284753 UIMC1 8165703 or 7911343 NM_014248 RBX1 03420, 04110, 8073334 04114, 04120, 04141, 04310, 04350, 04710, 05200, 05211 NR_003287 RN28S1 7942875 NM_177987 TUBB8 04145, 04540, 7911355 05130 NM_170601 SIAE 7944867 NM_001012708 KRTAP5-3 7945652 NR_029710 MIR193A 8006321 NM_000981 RPL19 3010 8006845 NM_003792 EDF1 8165309 NM_012217 TPSD1 7992191 NR_029824 MIR128-2 8078527 NM_003731 SSNA1 8159609 BC013044 DNAJA2 4141 7995379 NM_001037160 CYS1 8050232 NM_004352 CBLN1 8001329 NM_006160 NEUROD2 8014865 NM_001017 RPS13 3010 7946812 NM_017854 TMEM160 8037853 NM_152568 NKX6-3 8150433 NM_001417 EIF4B 03013, 04150 7963575 NM_003094 SNRPE 3040 8160033 NR_002715 RN7SL1 8040338 NM_016170 TLX2 8042896 NM_000307 POU3F4 8168567 NM_016057 COPZ1 7955896 NM_012322 LSM5 03018, 03040 8138912 AK302042 LOC440518 8027343 NM_000863 HTR1B 4080 8127692 NM_003512 HIST1H2AC 5322 8117372 NM_001080113 C14orf184 7980859 NR_024583 POM121L8P 8071168 NM_145232 CTU1 4122 8038782 AK123383 LOC642648 8076747 NM_032479 MRPL36 8110861 NM_007241 SNF8 4144 8016508 NM_016564 CEND1 7945536 NR_033335 SNORA70G 7964830 NM_144615 TMIGD2 8032782 NM_003538 HIST1H4A 5322 8117334 NM_016424 LUC7L3 8016733 NM_032231 FAM96A 7989611 NM_014206 C11orf10 7948606 NR_000009 SNORD4B 8005957 NM_001135086 PRSS41 7992716 AK125166 LOC441268 8141166 NR_001445 RN7SK 8120249 NM_001551 IGBP1 8168087 NM_005608 PTPRCAP 7949792 NM_145203 CSNK1A1L 04310, 04340 7971071 NM_023002 HAPLN4 8035646 NM_003542 HIST1H4C 5322 8117368 NM_001001521 UGP2 00040, 00052, 8052624 00500, 00520, 01100 NM_031210 SLIRP 7975989 NM_013299 SAC3D1 7941122 NM_001044370 MPPED1 8073623 NM_004175 SNRPD3 03040, 05322 8071920 NM_006327 TIMM23 7927548 NM_031213 FAM108A1 8032371 NM_001031 RPS28 3010 8025395, 8005471 or 7942824 BC033986 LOC440934 8048712 BC005079 C2orf42 8052834 BC001181 FAM173A 7992043 NM_000847 GSTA3 00480, 00980, 8127087 00982 NM_017900 AURKAIP1 8039923, 7911532 NM_001018138 NM_E2 00230, 00240, 8180388, 01100 8180389, 8180387 or 8180386 NM_001082575 RBFOX3 8018993 NM_015456 COBRA1 8159654 NM_080603 ZSWIM1 8063074 NM_001029 RPS26 3010 8007797 NM_006088 TUBB2C 04145, 04540, 8165496 05130 NM_004609 TCF15 8064370 NM_181887 UBE2D3 04120, 04141 8180330, 8180335, 8180331, 8180334, 8180333, 8180329 or 8180332 NM_015965 NDUFA13 00190, 05010, 8027205 05012, 05016 NM_178536 LCN12 8159501 NM_032753 RAX2 8032601 NM_016060 MED31 8011968 NR_003666 SPDYE7P 8133209 AK125308 LOC100129484 8137962 NR_003051 RMRP 8161024 NM_005319 HIST1H1C 8124397 NM_003550 MAD1L1 04110, 04914 8137805 ENST00000427835 C20orf61 8065013 NM_144999 LRRC45 8010719 NM_006087 TUBB4 04145, 04540, 8025051 05130 NR_029583 MIR197 7903717 NM_002307 LGALS7 8036584 or 8028546 NM_014370 SRPK3 8170753 AK098732 TRAP1 7992954 NM_001348 DAPK3 05200, 05219, 8032718 NM_022061 MRPL17 7946267 NM_002528 NTHL1 3410 7998692 NM_032527 ZGPAT 8064156 NM_006858 TMED1 8034101 NM_005274 GNG5 4062 8174509 NM_022363 LHX5 7966631 NM_001037495 DYNLL1 4962 7967067 NM_021104 RPL41 3010 7957530 AK095987 FLJ38668 8054449 NM_181838 UBE2D2 04120, 04141, 8108435 05131 NM_002003 FCN1 8165011 NM_016589 TIMMDC1 8081867 NM_020412 CHMP1B 4144 8020179 NR_026800 KIAA0125 7977440 NM_014674 EDEM1 4141 8085116 NM_138417 KTI12 7916130 NM_012315 KLK9 8038716 NR_029681 MIR140 7997008 NM_173547 TRIM65 8018502 NM_003577 UTF1 7931553 NM_138574 HDGFL1 8117172 NM_018942 HMX1 8104136 NM_001080495 TNRC18 8137959 NM_002066 GML 8148565 NM_001168 BIRC5 05200, 05210 8018860 NM_020064 BARHL1 8158912 NM_021012 KCNJ12 8005726 NM_001007595 C2CD4B 7989473 NM_031899 GORASP1 8086317 NM_019082 DDX56 8139392 AY730278 CENPVL1 8172715 or 8167652 NM_175064 SPDYE1 8140424 NM_001033113 ENTPD8 00230, 00240, 8165538 NM_006770 MARCO 4145 8044773 AK094921 LOC100131763 8049950 NM_001126128 PROK2 8088813 NM_016063 HDDC2 8129363 NM_182532 TMEM61 7901687 NR_024591 POM121L1P 8074714 NM_020180 CELF4 8022952 NM_012394 PFDN2 7921786 NM_006312 NCOR2 4330 7959772 NM_001804 CDX1 8109226 NR_026676 RPS2P32 8131869 NM_001002 RPLP0 3010 8109750 NR_002781 TSPY26P 8065603 NM_003001 SDHC 00020, 00190, 8011212 01100, 05010, 05012, 05016, NM_002669 PLRG1 3040 8103289 NM_006801 KDELR1 5110 8038078 NM_015971 MRPS7 8009784 NM_003684 MKNK1 04010, 04910 7915846 NM_018047 RBM22 3040 8115168 NM_012249 RHOQ 4910 8041808 NM_001172743 RAI2 8171539 NM_016305 SS18L2 8079074 NM_001113201 NACA 7964262 NM_001144936 C11orf95 7949015 NM_012452 TNFRSF13B 04060, 04672, 8013061 05340 NM_004939 DDX1 8040386 NM_003493 HIST3H3 5322 7924884 NM_001013 RPS9 3010 8180398 NM_006356 ATP5H 00190, 01100, 8018288 05010, 05012, 05016 NM_145657 GSX1 7968260 NM_182702 PRSS42 8086683 NM_005574 LMO2 7947450 NM_003926 MBD3 8032275 NM_024816 RABEP2 8000616 NM_003859 DPM1 00510, 01100 8067017 NM_022097 CHP2 04010, 04020, 7994123 04114, 04210, 04310, 04360, 04370, 04650, 04660, 04662, 04720, 05010, 05014 NM_014582 OBP2A 8180231 L20860 SEPT5-GP1BB 8071272 NM_016602 CCR10 04060, 04062, 8015681 04672 NM_006292 TSG101 4144 7947015 NM_003910 BUD31 3040 8134589 NM_005034 POLR2K 00230, 00240, 8147654 01100, 03020, 05016

In another embodiment, cycling hypoxia markers are selected from the list of the cycling hypoxia markers of Table 5 below, as well as their variants, fragments or equivalents. Table 5 comprises cycling hypoxia markers identified in the conditions of the Example and which are the 100 probe sets with the lowest FDR corrected p-values average over 200 data resampling, corresponding to 96 annoted genes. Table 5 thus comprises 96 cycling hypoxia markers.

TABLE 5 GeneBank Name of the Accession Number marker Pathways Probeset NM_001168 BIRC5 05200, 05210 8018860 NM_032527 ZGPAT 8064156 NM_012322 LSM5 03018, 03040 8138912 NM_012394 PFDN2 7921786 NM_002003 FCN1 8165011 NM_001113201 NACA 7964262 NM_005608 PTPRCAP 7949792 NM_006858 TMED1 8034101 NM_001551 IGBP1 8168087 NM_001417 EIF4B 03013, 04150 7963575 NM_005319 HIST1H1C 8124397 NM_031210 SLIRP 7975989 NM_000863 HTR1B 4080 8127692 NM_000847 GSTA3 00480, 00980, 8127087 00982 NM_013299 SAC3D1 7941122 NM_002528 NTHL1 3410 7998692 NM_001044370 MPPED1 8073623 NM_006160 NEUROD2 8014865 NM_021012 KCNJ12 8005726 NM_022363 LHX5 7966631 NM_017854 TMEM160 8037853 NM_018942 HMX1 8104136 NM_014206 C11orf10 7948606 NM_006770 MARCO 4145 8044773 NM_006292 TSG101 4144 7947015 NM_003577 UTF1 7931553 NM_032338 LLPH 7956876 NM_003512 HIST1H2AC 5322 8117372 NM_004352 CBLN1 8001329 NM_015965 NDUFA13 00190, 05010, 8027205 05012, 05016 NM_016170 TLX2 8042896 NM_017900 AURKAIP1 7911532 or 8039923 BC001181 FAM173A 7992043 NM_080603 ZSWIM1 8063074 NM_012217 TPSD1 7992191 NM_181838 UBE2D2 04120, 04141, 8108435 05131 NM_003792 EDF1 8165309 NM_022061 MRPL17 7946267 NM_016564 CEND1 7945536 NM_003731 SSNA1 8159609 NM_001031 RPS28 3010 8005471, 8025395 or 7942824 NM_014370 SRPK3 8170753 NM_001348 DAPK3 05200, 05219, 8032718 NM_001037495 DYNLL1 4962 7967067 NM_015456 COBRA1 8159654 NM_003001 SDHC 00020, 00190, 8011212 01100, 05010, 05012, 05016 NM_016060 MED31 8011968 NR_026800 KIAA0125 7977440 NM_007241 SNF8 4144 8016508 NM_000307 POU3F4 8168567 NM_031899 GORASP1 8086317 BC005079 C2orf42 8052834 NM_014248 RBX1 03420, 04110, 8073334 04114, 04120, 04141, 04310, 04350, 04710, 05200, 05211 NM_003684 MKNK1 04010, 04910 7915846 NM_004175 SNRPD3 03040, 05322 8071920 NM_031213 FAM108A1 8032371 NM_003493 HIST3H3 5322 7924884 NM_000981 RPL19 3010 8006845 NM_001017 RPS13 3010 7946812 NM_001144936 C11orf95 7949015 NM_015971 MRPS7 8009784 NM_005274 GNG5 4062 8174509 NM_005973 PRCC 7906235 NM_020412 CHMP1B 4144 8020179 NM_005574 LMO2 7947450 NM_004609 TCF15 8064370 NM_016057 COPZ1 7955896 NM_003550 MAD1L1 04110, 04914 8137805 NM_003538 HIST1H4A 5322 8117334 NM_003542 HIST1H4C 5322 8117368 NR_002312 RPPH1 7977507 BC018448 MALAT1 7949410 NM_152568 NKX6-3 8150433 NR_024583 POM121L8P 8071168 NM_032231 FAM96A 7989611 NM_001080113 C14orf184 7980859 NM_144615 TMIGD2 8032782 NM_032479 MRPL36 8110861 NM_182532 TMEM61 7901687 NM_138417 KTI12 7916130 BC033986 LOC440934 8048712 NM_001082575 RBFOX3 8018993 NM_032753 RAX2 8032601 NM_144999 LRRC45 8010719 NM_002307 LGALS7 8036584 or 8028546 NR_003666 SPDYE7P 8133209 NM_178536 LCN12 8159501 ENST00000427835 C20orf61 8065013 NM_173547 TRIM65 8018502 NM_033055 HIAT1 7903294 NM_001007595 C2CD4B 7989473 AK095987 FLJ38668 8054449 NM_016589 TIMMDC1 8081867 NM_144589 COMTD1 7934544 NM_145657 GSX1 7968260 NM_020180 CELF4 8022952

In another embodiment, cycling hypoxia markers are selected from the list of the 74 cycling hypoxia markers of Table 6 below, as well as their variants, fragments or equivalents. Table 6 comprises cycling hypoxia markers identified in the conditions of the Example and presenting an average FDR corrected p-value over 200 data resampling lower than 0.001.

TABLE 6 GeneBank Name of the Accession Number marker Pathways Probeset NR_002312 RPPH1 7977507 BC018448 MALAT1 7949410 AF284753 UIMC1 8165703 or 7911343 NM_014248 RBX1 03420, 04110, 8073334 04114, 04120, 04141, 04310, 04350, 04710, 05200, 05211 NR_003287 RN28S1 7942875 NM_177987 TUBB8 04145, 04540 7911355 05130 NM_170601 SIAE 7944867 NM_001012708 KRTAP5-3 7945652 NR_029710 MIR193A 8006321 NM_000981 RPL19 3010 8006845 NM_003792 EDF1 8165309 NM_012217 TPSD1 7992191 NR_029824 MIR128-2 8078527 NM_003731 SSNA1 8159609 BC013044 DNAJA2 4141 7995379 NM_001037160 CYS1 8050232 NM_004352 CBLN1 8001329 NM_006160 NEUROD2 8014865 NM_001017 RPS13 3010 7946812 NM_017854 TMEM160 8037853 NM_152568 NKX6-3 8150433 NM_001417 EIF4B 03013, 04150 7963575 NM_003094 SNRPE 3040 8160033 NR_002715 RN7SL1 8040338 NM_016170 TLX2 8042896 NM_000307 POU3F4 8168567 NM_016057 COPZ1 7955896 NM_012322 LSM5 03018, 03040 8138912 AK302042 LOC440518 8027343 NM_000863 HTR1B 4080 8127692 NM_003512 HIST1H2AC 5322 8117372 NM_001080113 C14orf184 7980859 NR_024583 POM121L8P 8071168 NM_145232 CTU1 4122 8038782 AK123383 LOC642648 8076747 NM_032479 MRPL36 8110861 NM_007241 SNF8 4144 8016508 NM_016564 CEND1 7945536 NR_033335 SNORA70G 7964830 NM_144615 TMIGD2 8032782 NM_003538 HIST1H4A 5322 8117334 NM_016424 LUC7L3 8016733 NM_032231 FAM96A 7989611 NM_014206 C11orf10 7948606 NR_000009 SNORD4B 8005957 NM_001135086 PRSS41 7992716 AK125166 LOC441268 8141166 NR_001445 RN7SK 8120249 NM_001551 IGBP1 8168087 NM_005608 PTPRCAP 7949792 NM_145203 CSNK1A1L 04310, 04340 7971071 NM_023002 HAPLN4 8035646 NM_003542 HIST1H4C 5322 8117368 NM_001001521 UGP2 00040, 00052, 8052624 00500, 00520, 01100 NM_031210 SLIRP 7975989 NM_013299 SAC3D1 7941122 NM_001044370 MPPED1 8073623 NM_004175 SNRPD3 03040, 05322 8071920 NM_006327 TIMM23 7927548 NM_031213 FAM108A1 8032371 NM_001031 RPS28 3010 8025395 or 8005471 BC033986 LOC440934 8048712 BC005079 C2orf42 8052834 BC001181 FAM173A 7992043 NM_000847 GSTA3 00480, 00980, 8127087 00982 NM_017900 AURKAIP1 8039923 NM_001018138 NME2 00230, 00240, 8180388 or 01100 8180389 NM_001082575 RBFOX3 8018993 NM_015456 COBRA1 8159654 NM_080603 ZSWIM1 8063074 NM_001029 RPS26 3010 8007797 NM_006088 TUBB2C 04145, 04540, 8165496 05130 NM_004609 TCF15 8064370 NM_181887 UBE2D3 04120 04141 8180330, 8180335, 8180331, 8180334 or 8180333

In another embodiment, cycling hypoxia markers are selected from the list of the 37 cycling hypoxia markers of Table 7 below, as well as their variants, fragments or equivalents. Table 7 comprises cycling hypoxia markers identified in the conditions of the Example and presenting an average FDR corrected p-value over 200 data resampling lower than 0.0001.

TABLE 7 GeneBank Name of the Accession Number marker Pathways Probeset NR_002312 RPPH1 7977507 BC018448 MALAT1 7949410 AF284753 UIMC1 8165703 or 7911343 NM_014248 RBX1 03420, 04110, 8073334 04114, 04120, 04141, 04310, 04350, 04710, 05200, 05211 NR_003287 RN28S1 7942875 NM_177987 TUBB8 04145, 04540, 7911355 05130 NM_170601 SIAE 7944867 NM_001012708 KRTAP5-3 7945652 NR_029710 MIR193A 8006321 NM_000981 RPL19 3010 8006845 NM_003792 EDF1 8165309 NM_012217 TPSD1 7992191 NR_029824 MIR128-2 8078527 NM_003731 SSNA1 8159609 BC013044 DNAJA2 4141 7995379 NM_001037160 CYS1 8050232 NM_004352 CBLN1 8001329 NM_006160 NEUROD2 8014865 NM_001017 RPS13 3010 7946812 NM_017854 TMEM160 8037853 NM_152568 NKX6-3 8150433 NM_001417 EIF4B 03013, 04150 7963575 NM_003094 SNRPE 3040 8160033 NR_002715 RN7SL1 8040338 NM_016170 TLX2 8042896 NM_000307 POU3F4 8168567 NM_016057 COPZ1 7955896 NM_012322 LSM5 03018, 03040 8138912 AK302042 LOC440518 8027343 NM_000863 HTR1B 4080 8127692 NM_003512 HIST1H2AC 5322 8117372 NM_001080113 C14orf184 7980859 NR_024583 POM121L8P 8071168 NM_145232 CTU1 4122 8038782 AK123383 LOC642648 8076747 NM_032479 MRPL36 8110861 NM_007241 SNF8 4144 8016508

In one embodiment, cycling hypoxia markers are selected from the list of the cycling hypoxia markers of Table 8 below, as well as their variants, fragments or equivalents.

TABLE 8 GeneBank Name of the Accession Number marker Pathways Probeset NM_001168 BIRC5 05200, 05210 8018860 NM_032527 ZGPAT 8064156 NM_012322 LSM5 03018, 03040 8138912 NM_012394 PFDN2 7921786 NM_002003 FCN1 8165011 NM_001113201 NACA 7964262 NM_005608 PTPRCAP 7949792 NM_006858 TMED1 8034101 NM_001551 IGBP1 8168087 NM_001417 EIF4B 03013, 04150 7963575

In one embodiment of the invention, the signature of the invention comprises or consists of at least 2, preferably at least 3, more preferably at least 5, and even more preferably at least 10 cycling hypoxia markers.

In one embodiment of the invention, the signature of the invention comprises or consists of 2, 3, 4, 5, 6, 7, 8, 9 or 10 cycling hypoxia markers.

In one embodiment of the invention, the signature of the invention comprises at least 10 markers selected from the list of Table 1, preferably from the list of Table 2, more preferably from the list of Table 3, even more preferably from the list of Table 4, still even more preferably from the list of Table 5, still even more preferably from the list of Table 6, still even more preferably from the list of Table 7, and still even more preferably from the list of Table 8.

In one embodiment of the invention, the signature of the invention comprises or consists of 8, 9 or 10 markers selected from the list of Table 1, preferably from the list of Table 2, more preferably from the list of Table 3, even more preferably from the list of Table 4, still even more preferably from the list of Table 5, still even more preferably from the list of Table 6, still even more preferably from the list of Table 7, and still even more preferably from the list of Table 8.

In one embodiment of the invention, the signature of the invention comprises at least 3 markers. In one embodiment of the invention, the signature of the invention comprises one, two or three of BIRC5, IGBP1 and EIF4B. In one embodiment of the invention, the signature of the invention comprises at least the three markers BIRC5, IGBP1 and EIF4B. In one embodiment of the invention, the signature of the invention consists in the three markers BIRC5, IGBP1 and EIF4B.

In one embodiment, the signature of the invention comprises or consists of 1, 2 or 3 markers selected from the list of Table 8, preferably BIRC5, IGBP1 and/or EIF4B, and 5, 6, 7, 8, or 9 markers selected from the list of Table 1, preferably from the list of Table 2, more preferably from the list of Table 3, even more preferably from the list of Table 4, still even more preferably from the list of Table 5, still even more preferably from the list of Table 6, still even more preferably from the list of Table 7, and still even more preferably from the list of Table 8.

In one embodiment, the signature of the invention comprises or consists of 1 marker selected from the list of Table 8, and 1, 2, 3, 4, 5, 6, 7, 8, or 9 markers selected from the list of Table 5. In another embodiment, the signature of the invention comprises or consists of 2 markers selected from the list of Table 8, and 1, 2, 3, 4, 5, 6, 7, or 8 markers selected from the list of Table 5. In another embodiment, the signature of the invention comprises or consists of 3 markers selected from the list of Table 8, and 1, 2, 3, 4, 5, 6, or 7 markers selected from the list of Table 5. In another embodiment, the signature of the invention comprises or consists of 4 markers selected from the list of Table 8, and 1, 2, 3, 4, 5, or 6 markers selected from the list of Table 5. In another embodiment, the signature of the invention comprises or consists of 5 markers selected from the list of Table 8, and 1, 2, 3, 4, or 5 markers selected from the list of Table 5. In another embodiment, the signature of the invention comprises or consists of 6 markers selected from the list of Table 8, and 1, 2, 3, or 4 markers selected from the list of Table 5. In another embodiment, the signature of the invention comprises or consists of 7 markers selected from the list of Table 8, and 1, 2, or 3 markers selected from the list of Table 5. In another embodiment, the signature of the invention comprises or consists of 8 markers selected from the list of Table 8, and 1, or 2 markers selected from the list of Table 5. In another embodiment, the signature of the invention comprises or consists of 9 markers selected from the list of Table 8, and 1 marker selected from the list of Table 5.

In one embodiment, the signature of the invention comprises or consists of the 8 markers BIRC5, LMO2, NTHL1, RPS13, SNF8, LSM5, NACA and RPS28.

In another embodiment, the signature of the invention comprises or consists of the 9 markers BIRC5, C14orf156, LSM5, DYNLL1, SNF8, RPS28, RPS13, NACA and CHMP1B.

In another embodiment, the signature of the invention comprises or consists of the 9 markers BIRC5, EIF4B, C14orf156, LSM5, DYNLL1, SNF8, RPS28, RPS13 and NACA.

In a preferred embodiment, the signature of the invention comprises or consists of 10 markers selected from the list of Table 8, their variants, fragments and equivalents. More preferably, the signature comprises or consists of the 10 markers of Table 8, i.e. BIRC5, ZGPAT, LSM5, PFDN2, FCN1, NACA, PTPRCAP, TMED1, IGBP1 and EIF4B.

In one embodiment, the signature of the invention comprises or consists of the 9 markers LMO2, NTHL1, RPS13, SNF8, RPS28, MRPL17, TSG101, DYNLL1 and MKNK1.

In another embodiment, the signature of the invention comprises or consists of the 10 markers EIF4B, LMO2, NTHL1, RPS13, SNF8, RPS28, MRPL17, TSG101, DYNLL1 and MKNK1.

In another embodiment, the signature of the invention comprises or consists of the 10 markers BIRC5, EIF4B, LMO2, NTHL1, RPS13, SNF8, RPS28, MRPL17, TSG101 and DYNLL1.

In one embodiment, the signature of the invention does not consist of markers selected from the group consisting of PTPRCAP, HIST1H1C, C11orf10, HIST1H2AC, SSNA1, RPS28, RBX1, RPS13, MAD1L1, HIST1H4A and HIST1H4C.

The present invention also relates to a signature as hereinabove described, for the prognosis of cancer in a subject, wherein the signature of the invention is a signature of cycling hypoxia, i.e. comprises markers whose expression is different between a normoxic condition and a cycling hypoxia condition.

The present invention further relates to a non-invasive method for the prognosis of cancer in a subject, wherein said method comprises assessing the expression of markers in a sample of said subject, whose expressions are different between a normoxic condition and a cycling hypoxia condition. In one embodiment, the markers whose expressions are different between a normoxic condition and a cycling hypoxia condition together form a signature according to the invention.

In one embodiment of the invention, the method of the invention is for determining a personalized course of treatment of the subject. Indeed, according to the prognosis obtained, a personalized treatment may be administered to the subject.

In one embodiment of the invention, the expression of at least 2, preferably of at least 3, more preferably of at least 5, and even more preferably of at least 10 markers is assessed.

The present invention also relates to a signature as hereinabove described, wherein said signature is a predictive signature and is a signature of cycling hypoxia, i.e. comprises markers whose expression is different between a normoxic condition and a cycling hypoxia condition.

The present invention further relates to a non-invasive method for predicting or anticipating the response of a subject, preferably of a patient, to a specific treatment, wherein said method comprises assessing the expression of markers in a sample of said subject, whose expressions are different between a normoxic condition and a cycling hypoxia condition. In one embodiment, the markers whose expressions are different between a normoxic condition and a cycling hypoxia condition together form a predictive signature according to the invention.

In one embodiment of the invention, the method of the invention is for determining a personalized course of treatment of the subject. Indeed, according to the result obtained with the predictive signature, a personalized treatment may be administered to the subject.

In one embodiment of the invention, the expression of at least 2, preferably of at least 3, more preferably of at least 5, and even more preferably of at least 10 markers is assessed.

In one embodiment, the subject is diagnosed with cancer. In another embodiment, the subject is at risk of cancer. Examples of risks include, but are not limited to, familial history of cancer, genetic predisposition to cancer, environmental risks such as, for example, exposure to carcinogenic chemicals or other types of carcinogenic agents, diet, clinical factors such as, for example, hormonal deregulation or presence of another cancer-inducing disease, and the like.

In one embodiment, the subject is a cancer patient. In one embodiment, the subject is a patient with precancerous lesions or adenoma.

According to this embodiment, the signature or the non-invasive method may be for predicting overall survival of the subject, wherein the overall survival refers to the survival at 2 years, preferably at 3, 5, 8 years, more preferably at 10 years.

Still according to this embodiment, the signature or the non-invasive method may be for identifying patients who could benefit from a specific treatment, such as, for example, a chemotherapeutic treatment.

Still according to this embodiment, the signature or the non-invasive method may be for assessing the likelihood of a beneficial response of the patient to a specific anti-cancer treatment. The signature or the non-invasive method of the invention may also be for predicting the resistance of a patient to a specific anti-cancer treatment.

Still according to this embodiment, the signature or the non-invasive method of the invention may be for classifying a patient as a good prognosis or poor prognosis patient, wherein a good prognosis means that a patient is expected to have no distant metastases of a tumor within 2, preferably 3, 5, 8 or 10 years, and a poor prognosis means that a patient is expected to have distant metastases of a tumor within 2, preferably 3, 5, 8 or 10 years.

In another embodiment, signature or the non-invasive method of the invention may be for classifying a patient as a progression-free survival (PFS) patient, wherein progression-free survival means that the cancer does not get worse.

In a first embodiment, the subject previously received an anticancer treatment. In another embodiment, the subject did not receive any anticancer treatment. Examples of treatment include, but are not limited to, surgery for removing the tumor, chemotherapy and/or radiotherapy.

In one embodiment, the subject was previously treated for a cancer.

In one embodiment, the subject is considered as substantially healthy as regard to this cancer, i.e. the treatment is considered to have been successful.

According to this embodiment, the signature or the non-invasive method may be for assessing the likelihood of distal recurrence of the cancer. In one embodiment, distal recurrence refers to recurrence within 2 years, preferably within 3, 5, 8 years, more preferably within 10 years. In one embodiment, the term “recurrence” may refer to the reappearance of cancer (preferably of a tumor) either within the same organ or elsewhere in the body.

According to this embodiment, the signature or the non-invasive method may be for predicting overall survival of the subject, wherein the overall survival refers to the survival at 2 years, preferably at 3, 5, 8 years, more preferably at 10 years.

In one embodiment of the invention, the cancer is a neoplasm, i.e. a cancer characterized by the presence of at least one malignant tumor.

Examples of cancers include, but are not limited to, breast cancer, prostate cancer, lung cancer, colon cancer, cervix cancer, prostate cancer, brain cancer, liver cancer, kidney cancer and connective tissue cancer.

In one embodiment, the cancer may originate in the bladder, blood, bone, bone marrow, brain, breast, cervic area, colon, connective tissue, esophagus, eye and periocular tissues including subconjunctival tissues, duodenum, small intestine, large intestine, rectum, anus, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, pancreas, prostate, skin, stomach, testis, tongue, or uterus.

Examples of cancer include, but are not limited to, fibrosarcoma, carcinoma, adenocarcinoma, lymphoma, blastoma, hepatoma, sarcoma, and leukemia. More particular examples of such cancers include squamous cell cancer, lung cancer (including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, such as, for example, pancreatic carcinoma, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, such as, for example, colon adenocarcinoma (including a colon adenocarcinoma grade II), colorectal cancer, such as, for example, colorectal carcinoma, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, such as, for example, prostate adenocarcinoma, vulval cancer, thyroid cancer, osteosarcoma, neuroblastoma, hepatic carcinoma and various types of head and neck cancer, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; Burkitt's lymphoma; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome.

Other examples of cancers include, but are not limited to, adenocarcinoma, such as, for example, breast adenocarcinoma, prostate adenocarcinoma, liver adenocarcinoma or colorectal adenocarcinoma; ductal carcinoma, such as, for example, breast ductal carcinoma; carcinoma such as, for example, colorectal carcinoma, kidney carcinoma or squamous cell carcinoma (such as, for example, squamous cell carcinoma of the cervix); glioblastoma; hepatocellular carcinoma; hepatoma; or fibrosarcoma.

In one embodiment of the invention, the cancer is breast cancer, and the patient may be classified in different subgroups determined on the basis of clinicopathologic criteria. In one embodiment, the breast cancer patient is node negative or node positive. In another embodiment, the breast cancer patient is ER+ or ER−, wherein ER stands for estrogens receptor. In another embodiment, the breast cancer patient is HER2+ or HER2−, wherein HER2 stands for Human Epidermal Growth Factor Receptor-2. In one embodiment, the breast cancer patient is ER+/HER2−, ER−/HER2− or HER2+. In another embodiment, the breast cancer patient is ER+/HER2− node negative. In another embodiment, the breast cancer patient is ER+/HER2− node negative and did not receive any anticancer treatment.

In another embodiment of the invention, the cancer is colorectal cancer and the patient may be classified in different subgroups determined on the basis of clinicopathologic criteria, according to the American Joint Committee on Cancer (AJCC). In one embodiment, the colorectal cancer is a submucosa and muscularis propria tumor (stage I or 1). In another embodiment, the colorectal cancer is a tumor invading through the muscularis propria (stage II or 2). In another embodiment, the colorectal cancer is node positive (stage III or 3). In another embodiment, the colorectal cancer is associated with distant metastases (stage IV or 4).

In one embodiment of the invention, the non-invasive method of the invention for the prognosis of cancer in a subject comprises determining the expression profile of markers of a signature of the invention in a sample of said subject.

According to a preferred embodiment, the sample was previously taken from the subject, i.e. the method of the invention does not comprise a step of recovering a sample from the subject. Consequently, according to this embodiment, the method of the invention is a non-invasive method.

In one embodiment of the invention, the sample is a biopsy sample or a fine-needle aspirate. In one embodiment, the biopsy or the fine-needle aspiration is a biopsy or a fine-needle aspiration of the mass of cells suspected to be a tumor. In another embodiment, when a tumor has already been identified, the biopsy or the fine-needle aspiration is a biopsy or a fine-needle aspiration of this tumor.

In another embodiment of the invention, the sample is a sample of a bodily fluid. Examples of bodily fluids include, but are not limited to, blood, plasma, serum, lymph, ascetic fluid, cystic fluid, urine, bile, nipple exudate, synovial fluid, bronchoalveolar lavage fluid, sputum, amniotic fluid, peritoneal fluid, cerebrospinal fluid, pleural fluid, pericardial fluid, semen, saliva, sweat and alveolar macrophages.

In one embodiment of the invention, the non-invasive method of the invention comprises a step of comparing the expression profile of the markers of the signature of the invention measured in the sample of the subject with a reference expression profile, measured in a reference sample.

A reference expression profile can be relative to an expression profile derived from population studies, including without limitation, such subjects having similar age range, subjects in the same or similar ethnic group, similar cancer history and the like.

In one embodiment, the reference expression profile is constructed using algorithms and other methods of statistical and structural classification.

In one embodiment of the invention, the reference expression profile is derived from the measurement of the expression profile of markers of a signature of the invention in a control sample derived from one or more substantially healthy subjects. As used herein, a “substantially healthy subject” has not been previously diagnosed or identified as having or suffering from cancer.

In one embodiment of the invention, the reference expression profile is derived from the measurement of the expression profile of markers of a signature of the invention in a reference sample derived from a healthy tissue or sample of the same subject, whereas the expression profile to be compared was measured in a sample taken from a suspect mass of cells (i.e. from the suspected tumor) within the body of the subject.

In one embodiment of the invention, the reference expression profile is derived from the previous measurement of the expression profile of markers of a signature of the invention in a reference sample derived from the same subject, such as, for example, the expression profile measured one month before, preferably six months before, more preferably one year before or more.

In another embodiment of the invention, the reference expression profile is derived from the measurement of the expression profile of markers of a signature of the invention in a reference population. In one embodiment, the reference sample is thus derived from a reference population.

In one embodiment, the reference population comprises substantially healthy subjects, preferably at least 50, more preferably at least 100, more preferably at least 200 and even more preferably at least 500 substantially healthy subjects.

In another embodiment, the reference population comprises subjects diagnosed with cancer, preferably at least 100, more preferably at least 250, more preferably at least 500 subjects diagnosed with cancer.

In another embodiment of the invention, the reference expression profile is derived from the measurement of the expression profile in a reference sample derived from one or more subjects who are diagnosed or identified as having or suffering from cancer.

In one embodiment, the reference expression profile corresponds to the mean expression profile of the markers of the signature of the invention measured in the reference population.

In one embodiment of the invention, the reference expression profile corresponds to the median expression profile of the markers of the genetic signature of the invention measured in the reference population.

In one embodiment of the invention, the expression of the cycling hypoxia markers corresponds to the transcription level (i.e. expression of the RNA), or to the translation level (i.e. expression of the protein) of the marker.

In one embodiment of the invention, the expression of the cycling hypoxia markers is assessed at the protein level. Methods for determining a protein level in a sample are well-known in the art. Examples of such methods include, but are not limited to, immunohistochemistry, Multiplex methods (Luminex), western blot, enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, fluorescent-linked immunosorbent assay (FLISA), enzyme immunoassay (EIA), radioimmunoassay (RIA) and the like.

In another embodiment of the invention, the expression of the cycling hypoxia markers is assessed at the RNA level. Methods for assessing the transcription level of a marker are well known in the prior art. Examples of such methods include, but are not limited to, RT-PCR, RT-qPCR, Northern Blot, hybridization techniques such as, for example, use of microarrays, and combination thereof including but not limited to, hybridization of amplicons obtained by RT-PCR, sequencing such as, for example, next-generation DNA sequencing (NGS) or RNA-seq (also known as “Whole Transcriptome Shotgun Sequencing”) and the like.

In one embodiment, the non-invasive method comprises the steps of:

-   -   extracting total RNA from the sample from the subject,     -   retro-transcribing these total RNA, thereby obtaining total         cDNA,     -   specifically amplifying by PCR, preferably by qPCR, the cDNA         corresponding to the cycling hypoxia markers of the signature of         the invention, thereby determining the expression profile of the         markers of the signature, and     -   comparing said expression profile with a reference expression         profile determined in a reference sample.

In one embodiment, the expression profile of markers of the signature of the invention is measured using a polynucleotide microarray, so that the expression profiles of each of the markers of the signature of the invention are simultaneously measured.

In one embodiment, the non-invasive method comprises the steps of:

-   -   extracting total RNA from the sample from the subject,         retro-transcribing these total RNA, thereby obtaining total cDNA         from the sample, and labeling said total cDNA,     -   extracting total RNA from the reference sample,         retro-transcribing these total RNA, thereby obtaining total cDNA         from the reference sample, and labeling said total cDNA with a         different label that the one used for the total cDNA of the         sample from the subject,     -   applying the total cDNA from the sample from the subject, and         the total cDNA from the reference sample, on a microarray, and     -   identifying markers which are differentially expressed between         the sample from the subject and the reference sample, based on         differential hybridization profile.

In one embodiment, the non-invasive method comprises the steps of:

-   -   in a first step, extracting total RNA from the reference sample,         retro-transcribing these total RNA, thereby obtaining total cDNA         from the reference sample, and labeling said total cDNA,     -   applying the total cDNA from the reference sample on a         microarray, thereby obtaining a reference hybridization profile,     -   in a second, preferably subsequent step, extracting total RNA         from the sample from the subject, retro-transcribing these total         RNA, thereby obtaining total cDNA from the sample, and labeling         said total cDNA,     -   applying the total cDNA from the sample from the subject on         another microarray, thereby obtaining a sample hybridization         profile, and     -   identifying markers which are differentially expressed between         the sample from the subject and the reference sample, based on         the differences of both hybridization profiles.

In one embodiment of the invention, the labeling of total cDNA is performed using fluorochromes, such as, for example, Cy3 and Cy5.

In one embodiment, the non-invasive method comprises the steps of:

-   -   extracting total RNA from the sample from the subject,         retro-transcribing these total RNA, thereby obtaining total cDNA         from the sample, and sequencing the total cDNA from the sample         from the subject,     -   extracting total RNA from the reference sample,         retro-transcribing these total RNA, thereby obtaining total cDNA         from the reference sample, and sequencing the total cDNA from         the reference sample, and     -   comparing the results of the cDNA sequencing and identifying         markers which are differentially expressed between the sample         from the subject and the reference sample.

In another embodiment, the non-invasive method comprises the steps of:

-   -   extracting total RNA from the sample from the subject, and         sequencing the total RNA, preferably the total mRNA, from the         sample from the subject,     -   extracting total RNA from the reference sample, and sequencing         the total RNA, preferably the total mRNA from the reference         sample, and     -   comparing the results of the RNA, preferably mRNA, sequencing         and identifying markers which are differentially expressed         between the sample from the subject and the reference sample.

In one embodiment of the invention, a marker of the invention is considered as differentially expressed in the sample from the subject as compared to a reference sample if both expression levels differ by a factor of at least 1.1, preferably at least 1.5, more preferably at least 2 and even more preferably at least 5.

In one embodiment of the invention, the post-translational modifications of a marker of the invention corresponds to a modification selected from the list comprising or consisting of phosphorylation, myristoylation, palmitoylation, isoprenylation, glypiation, lipoylation, O-, N- or S-acylation, alkylation, glycosylation, malonylation, hydroxylation, nucleotide addition, oxidation, sumoylation, ubiquitination, citrullination, deamidation, formation of disulfide bridges, proteolytic cleavage, racemization and the like.

Examples of methods for assessing post-translational modifications of a protein or peptide are well-known from the skilled artisan and include, but are not limited to, mass spectroscopy, methods using antibodies directed against the post-translational modification including, but not limited to, immunoblotting, immunoprecipitation, bead-based multiplexing, Eastern blotting, and the like.

The present invention also relates to a kit for measuring the expression profile of markers of the signature of the invention, and/or for implementing the non-invasive method of the invention. In one embodiment, the kit comprises means for determining the expression of the cycling hypoxia markers of the signature of the invention.

In one embodiment of the invention, the expression profile is measured at the protein level, and the kit of the invention comprises means for total protein extraction, as well as antibodies for detecting the cycling hypoxia markers of the invention.

The present invention also relates to a kit for determining the post-translational modification profile of markers of the signature of the invention, and/or for implementing the non-invasive method of the invention. In one embodiment, the kit comprises means for determining the post-translational modification of the cycling hypoxia markers of the genetic signature of the invention.

In another embodiment, the expression profile is measured at the RNA level, and the kit of the invention comprises means for total RNA extraction, means for reverse transcription of total RNA, and means for quantifying the expression of RNA corresponding to the cycling hypoxia markers of the invention.

In one embodiment, the means for determining the expression of the cycling hypoxia markers are PCR primers, preferably qPCR primers, specific for said cycling hypoxia markers. In one embodiment, said means for determining the expression of the cycling hypoxia markers are probes to detect qPCR amplicons obtained with qPCR primers as hereinabove described.

In one embodiment, said means for quantifying the expression of RNA corresponding to the cycling hypoxia markers of the invention is PCR, preferably qPCR.

Examples of set of primers and probes that may be used for quantifying the expression of the cycling hypoxia markers of Table 8 are shown in the Table 9 below:

The TaqMan gene expression assay references can be found on http://www.invitrogen.com/site/us/en/home/Products-and-Services/Applications/PCR/real-time-per/real-time-per-assays/taqman-gene-expression/single-tube-taqman-gene-expression-analysis.html.

TABLE 9 TaqMan gene expression assay GeneBank Name of the references Accession Number marker (primer/probe set) NM_001168 BIRC5 Hs04194392_s1 NM_032527 ZGPAT Hs00738790_m1 NM_012322 LSM5 Hs01123609_g1 NM_012394 PFDN2 Hs00276171_m1 NM_002003 FCN1 Hs00157572_m1 NM_001113201 NACA Hs01903640_uH NM_005608 PTPRCAP Hs02519237_s1 or Hs00174778_m1 NM_006858 TMED1 Hs00183648_m1 or Hs00970159_g1 NM_001551 IGBP1 Hs00426831_mH NM_001417 EIF4B Hs01903212_gH or Hs00251278_s1

In one embodiment of the invention, set of primers and probe that are used for quantifying the expression of the cycling hypoxia marker BIRC5 are the following sequences: AGGGCTGAAGTCTGGCGTAA (forward primer, SEQ ID NO:1), AACAATCCACCCTGCAGCTCTA (reverse primer, SEQ ID NO:2) and ATGATGGATTTGATTCGC (probe, SEQ ID NO:3).

In one embodiment of the invention, set of primers and probe that are used for quantifying the expression of the cycling hypoxia marker NACA are the following sequences: CCACCCCTAAATCTGCTGGAA (forward primer, SEQ ID NO:4), TCCAGACCCCTTGTTGTTCTTC (reverse primer, SEQ ID NO:5) and CCCTGTCCCAACCC (probe, SEQ ID NO:6).

In one embodiment of the invention, set of primers and probe that are used for quantifying the expression of the cycling hypoxia marker IGBP1 are the following sequences: GTCCGCGCTCGCCTAAT (forward primer, SEQ ID NO:7), GAGAGAGGAACCCGGAAGATCT (reverse primer, SEQ ID NO:8) and CTTTATCAAGGTTGCCTTTG (probe, SEQ ID NO:9).

In one embodiment of the invention, the kit of the invention also comprises primers for amplifying reference genes. Reference genes are genes expressed at a constant level among different tissues and/or conditions. Examples of reference genes include, but are not limited to, β-actin, genes encoding ribosomal proteins and the like.

In one embodiment of the invention, the kit of the invention comprises means for total RNA extraction, means for reverse transcription of total RNA, and reagents for carrying out a quantitative PCR as hereinabove described (such as, for example, primers, buffers, enzyme, and the like). In one embodiment, the kit of the invention also comprises a reference sample.

In one embodiment of the invention, the kit of the invention comprises DNA probes, which may be hybridized to the qPCR amplicons to detect said cycling hypoxia marker.

In one embodiment, the means for determining the expression of the markers of the signature is a microarray comprising probes specific for said cycling hypoxia markers.

In one embodiment, said means for quantifying the expression of RNA corresponding to the cycling hypoxia markers of the invention is a microarray. The present invention thus also relates to microarrays for measuring the RNA expression profile of markers of the signature of the invention, and/or for implementing the non-invasive method of the invention.

In one embodiment of the invention, the microarray of the invention comprises DNA probes, which may be hybridized to the retro-transcribed RNA corresponding to the cycling hypoxia markers of the invention.

In one embodiment of the invention, the microarray of the invention comprises probes specific of at least 3, 5, 10, 15, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 750, 1000, or at least 1350 cycling hypoxia markers of the invention, and up to the 1379 cycling hypoxia markers of Table 1.

In one embodiment of the invention, the microarray of the invention comprises probes specific of the 1379 markers of Table 1, and/or of the 651 markers of Table 2, and/or of the 298 markers of Table 3, and/or of the 167 markers of Table 4, and/or of the 96 markers of Table 5, and/or of the 74 markers of Table 6, and/or of the 37 markers of Table 7, and/or of the 10 markers of Table 8.

Examples of probes specific of the cycling hypoxia markers of the invention include, but are not limited to those corresponding to the probesets shown in the columns “probeset” of Tables 1 to 8, wherein numbers correspond to Affymetrix references. The oligonucleotide sequence corresponding to the Affymetrix references may be easily found on the product support page of Affymetrix (https://www.affymetrix.com/user/login.jsp?toURL=/analysis/netaffx/xmlquery ex.affx ?netaffx=wtgene_transcript) by selecting Human Gene 1.X ST.

In one embodiment of the invention, the microarray comprises probes specific of the 96 markers of Table 5.

In one embodiment of the invention, the microarray comprises probes specific of the 10 markers of Table 8.

In one embodiment, the microarray of the invention also comprises probes for reference genes. Reference genes are genes expressed at a constant level among different tissues and/or conditions. Examples of reference genes include, but are not limited to, β-actin, genes encoding ribosomal proteins and the like.

In one embodiment, the microarray of the invention also comprises probes for quality control genes. Quality control genes expression allows verifying the quality of the microarray and/or of the cDNA applied on the microarray.

In one embodiment of the invention, the kit of the invention comprises means for total RNA extraction, means for reverse transcription of total RNA, and a microarray of the invention as well as buffers and materials for use thereof. In one embodiment, the kit of the invention also comprises a reference sample.

In one embodiment, the means for determining the expression of the markers of the signature is sequencing means, allowing sequencing total RNA, preferably mRNA, or total cDNA of the sample from the subject, preferably using high-throughput sequencing technologies, more preferably using the RNA-Seq technology.

Examples of means for total sequencing of cDNA of a sample include, but are not limited to, poly(T) oligos, poly(T) magnetic beads, probes for removing ribosomal RNA, reverse transcriptase, emulsion PCR buffers and reagents, bridge amplification buffers and reagents, ligase and the like.

In another embodiment of the invention, the non-invasive method of the invention also comprises a step of measuring clinical data. Examples of clinical data which may be relevant for the prognosis of cancer in a subject and/or for predicting the response of a subject, preferably of a patient, to a specific treatment include, but are not limited to, gender, age, size of the tumor, tumor histological grade, lymph node status, presence of a treatment, presence of metastases, specific expression profiles (such as, for example, expression status for estrogen receptor or for HER2 receptor), Nottingham grading system (NGS), Nottingham Prognostic Index (NPI), and the like.

In one embodiment of the invention, the non-invasive method of the invention comprises a step of combining the expression profiles of the markers of the signature of the invention and optionally of the value of clinical data as hereinabove described in a score.

In one embodiment, said combination is a mathematical combination in a mathematical function. Preferably, said mathematical function is a weighted sum. In one embodiment, the weighted sum is adjusted on the reference sample.

In one embodiment, the method of the invention comprises comparing the score obtained with a threshold value. In one embodiment, the threshold value corresponds to the score obtained in a reference population or in a reference sample. In another embodiment, the weighted sum is adjusted on the reference sample such that the threshold value is equal to 0.

In one embodiment, the score of the invention is a prognostic score, and may be used for the prognosis of cancer in the subject. In another embodiment, the score of the invention is a predictive score, and may be used for predicting the response of a subject, preferably of a patient, to a specific treatment.

The present invention thus also relates to a non-invasive method for the prognosis of cancer in a subject, or for predicting the response of a subject to a specific treatment, wherein said method comprises:

-   -   assessing the expression profiles of markers of a signature         comprising at least 2 cycling hypoxia markers in a sample from         said subject, and     -   mathematically combining the measured expression profiles in a         score.

The present invention presents the following advantages:

-   -   (i) As cycling hypoxia is a hallmark of a vast majority of         tumors, the signature of the invention allows the prognosis of         all tumor types, and of all neoplasms;     -   (ii) The prognosis method of the invention, based on the         identification of the signature of the invention, is easy and         rapid to implement, as the inventors showed that a signature of         the invention, comprising as few as about 10 markers, allows an         efficient prognosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a heatmap depicting transcripts from a signature of the invention (CycHyp) either underexpressed (green) or overexpressed (red) (centered to median values). Each column corresponds to a specific Human Gene 1.0 ST probeset; each line represents a specific cell line either maintained under normoxia (black label) or exposed to cycling hypoxia (red label); cell under normoxia and cycling hypoxia are perfectly separated in two distinct clusters, except for one cycling hypoxia sample in the normoxia cluster.

FIG. 2 is a combination of Kaplan-Meier survival curves of patients with primary breast cancer, as determined by using a signature of the invention (CycHyp). (A): All patients; (B): ER+/HER2− patients; (C): node-negative ER+/HER−2 patients; and (D): node-negative, untreated patients (DFS Mantel-Cox comparison).

FIG. 3 is a comparison of the prognostic potential of the CycHyp signature vs. Gene 70 (Mammaprint), Gene 76 and Oncotype Dx signatures to discriminate patients with progressing disease versus disease-free at 5-years. (A) Balance Classification Rate (BCR), i.e. the arithmetic average between specificity and sensitivity (also depicted) determined on the validation sets only (to avoid an optimistic bias if computed on the training set) [see text for p-values] and Concordance Index (CI) between high and low risk patients, [p<0.05 vs. Oncotype DX, p=0.07 vs. Gene70 and p=0.063 vs. Gene76]. (B.) Kaplan-Meier survival curves of node-negative, untreated ER+/HER2− patients, as determined by using the indicated signature (DFS Mantel-Cox comparison); hazard ratio (HR) for the prediction in high risk vs. low risk groups are presented with their associated confidence interval and p-values.

FIG. 4 is a combination of Kaplan-Meier survival curves of node-negative, untreated ER+/HER2− patients stratified by using a signature of the invention (CycHyp) to detect (A) false-positive patients among those identified at high risk based on the NPI nomenclature and (B) false-negative patients among those identified at low risk based on the NPI nomenclature (DFS Mantel-Cox comparison).

FIG. 5 is a combination of Kaplan-Meier survival curves of patients with primary breast cancer stratified at low or high risk according to a signature of the invention (CycHyp) or the NPI nomenclature (DFS Mantel-Cox comparison). (A): all patients; (B): ER+/HER2− patients; (C): node-negative ER+/HER2− patients; (D): node-negative, untreated ER+/HER2− patients.

FIG. 6 is a combination of Kaplan-Meier survival curves of patients with primary breast cancer stratified at low or high risk according to a 10-probesets signature (see Table 14) of the invention.

FIG. 7 is a combination of Kaplan-Meier survival curves of patients with primary breast cancer stratified at low or high risk according to a 10-probesets signature of the invention. This is an example of a 10-probesets signature selected from those shown in Table 11 without any overlap with the probes reported in Table 14. Note that the probesets for BIRC5 and NACA are different in Table 14 and Table 15.

FIG. 8 is a combination of Kaplan-Meier survival curves of patients with primary breast cancer stratified at low or high risk according to a 10-probesets signature of the invention. This is an example of a 10-probesets signature selected from those shown in Table 11 with a single one (BIRC5) overlapping with those reported in Table 14. Note that the probesets for NACA are different in Table 14 and Table 16.

FIG. 9 is a combination of Kaplan-Meier survival curves of patients with primary breast cancer stratified at low or high risk according to a 10-probesets signature of the invention. This is an example of a 10-probesets signature selected from those shown in Table 11 with two probesets (BIRC5 and EIF4B) overlapping with those reported in Table 14. Note that the probesets for NACA are different in Table 14 and Table 17.

FIG. 10 is a graph representing the power of discrimination in high vs. low risk groups (expressed as the logarithm of the p-values of the log rank) of the ContHyp (left) and CycHyp (right) signatures (see black dots) versus 1,000 randomly generated signatures of breast cancer patients (gray shapes depicting their distribution).

FIG. 11 is a combination of Kaplan-Meier survival curves of patients with primary breast cancer stratified at low or high risk according to a 10-probesets signature of the invention. This is an example of a 10-probesets signature (see Table 18′) selected from those shown in Table 11 without any overlap with the probes reported in Table 14.

FIG. 12 is a combination of Kaplan-Meier survival curves of patients with primary breast cancer stratified at low or high risk according to a 10-probesets signature of the invention. This is an example of a 10-probesets signature selected from those shown in Table 18 with a single one (EIF4B) overlapping with those reported in Table 14.

FIG. 13 is a combination of Kaplan-Meier survival curves of patients with primary breast cancer stratified at low or high risk according to a 10-probesets signature of the invention. This is an example of a 10-probesets signature selected from those shown in Table 18 with two probesets (EIF4B and BIRC5) overlapping with those reported in Table 14.

FIG. 14 is combination of Kaplan-Meier survival curves of node-negative, untreated ER+/HER2− patients stratified at low or high risk according to the ContHyp signature (DFS Mantel-Cox comparison).

FIG. 15 is a graph representing the power of discrimination in high vs. low risk groups (expressed as the logarithm of the p-values of the log rank) of the CycHyp signatures (see black dots) versus 1,000 randomly generated signatures of colorectal cancer patients (gray shapes depicting their distribution).

FIG. 16 is a combination of Kaplan-Meier survival curves of stage II colorectal cancer patients stratified at low or high risk according to the CycHyp signature.

FIG. 17 is a combination of Kaplan-Meier survival curve of patients with primary breast cancer stratified at low or high risk according to a 3-probesets signature (see Table 21) of the invention.

EXAMPLES

The present invention is further illustrated by the following examples.

Example 1 CycHyp Signature on Breast Cancer Patients Patients and Methods Tumor Cells

Twenty tumor cells (see Table 10 for details) were submitted to cycling hypoxia (CycHyp), i.e. 24 cycles of 30 min incubation under normoxia and 30 min incubation under hypoxic (1% O₂) conditions to reproduce the frequency of tumor hypoxic fluctuations, as previously reported (Dewhirst, Radiat Res 172:653-665, 2009).

TABLE 10 List of Human Tumor Cells used for Microarray Analysis. Cell line Organ Disease MCF-7 Breast Adenocarcinoma MDA-MB-231 Breast Adenocarcinoma T47D Breast Ductal carcinoma A549 Lung Carcinoma Widr Colon Colorectal adenocarcinoma HCT116^(WTP53) Colon Colorectal carcinoma HCT116^(−/) ^(—) ^(P53) Colon Colorectal carcinoma HT29 Colon Colorectal adenocarcinoma Colo-205 Colon Colorectal adenocarcinoma LoVo Colon Colorectal adenocarcinoma HCT15 Colon Colorectal adenocarcinoma SiHa Cervix Squamous cell carcinoma PC3 Prostate Adenocarcinoma U373 Brain Glioblastoma HepG2 Liver Hepatocellular carcinoma Hep3B Liver Hepatocellular carcinoma PLC/PRF/5 Liver Hepatoma SK-HEP-1 Liver Adenocarcinoma A498 Kidney Carcinoma HT1080 Connective tissue Fibrosarcoma

Identification of the Signature

mRNA extracts from each tumor cell cultured under both the above conditions (normoxia and cycling hypoxia) were analysed by hybridization on Human Gene 1.0 ST Affymetrix microarrays (GEO access number: GSE42416). The extent of the resulting tumor cell datasets (20 samples in each of the three conditions) led us to resort on a resampling mechanism to increase the robustness of the signatures to be identified. For every resampling experiment, a subset of 90% of the samples was chosen uniformly at random without replacement. Differentially expressed probesets were assessed on each subset according to a t-test and the corresponding p-values were reported. The 100 probesets with the lowest p-values, averaged over 200 resamplings, formed the CycHyp signature. All such expression differences were highly significant (p<10⁻⁴) after Benjamini-Hochberg FDR correction for the multiplicity of the test (Benjamini et al, J R Stat Soc 57:289-300, 1995). The 100 HGU1.0 ST probesets forming the CycHyp signature corresponded to 94 unique Entrez GeneID in the NCBI database, out of which 69 genes were available on the HGU133a platform (i.e., the technology used in most clinical studies considered here). Those 69 genes were represented by 87 HGU133a probesets. The few datasets collected on HGU133plus2 were reduced to the probesets also present on HGU133a, thus with an identical CycHyp signature of 87 probesets.

Patient Data Sets

All breast cancer expression data were summarized with MASS and represented in log 2 scale (except for GSE6532 already summarized with RMA). Breast cancer subtypes (ER+/HER2−, ER−/HER2− and HER2+) were identified with the genefu R package (Haibe-Kains et al, Genome Biol 11:R18, 2010). Disease-free survival at 5 years was used as the survival endpoint. The data from all patients were censored at 10 years to have comparable follow-up times across clinical studies (Haibe-Kains et al, Bioinformatics 24:2200-2208, 2008).

Prognostic Models of the Clinical Outcome

The VDX dataset (GSE2034 and GSE5327 from the GEO database) was considered as a reference because of its large number of node-negative untreated patients (Wang et al, Lancet 365:671-679, 2005). This dataset formed the training set used to estimate a prognostic model of the clinical outcome. A risk score for each patient was computed from a penalized Cox proportional hazards model implemented in the Penalized R package (Goeman, Biom J 52:70-84, 2010). Prediction into a high risk vs. low risk group resulted from a predefined threshold value on this risk score. The decision threshold was chosen on the training set to maximize the specificity and sensitivity of the discrimination between patients with progressing disease versus disease-free patients at 5 years. Following the methodology described by Haibe-Kains et al. (Haibe-Kains et al, Bioinformatics 24:2200-2208, 2008), all other datasets were used as validations to assess the prognostic performances on independent samples. Performance metrics included the balanced classification rate (BCR), i.e. the arithmetic average between specificity and sensitivity (determined on the validation sets only to avoid an optimistic bias if computed on the training set), the concordance index (CI) (Harrell et al, Stat Med 15:361-387, 1996) and the hazard ratio (HR) (Cox, J R Stat Soc 34:187-220, 1972) for the prediction in high risk vs. low risk groups, with their associated confidence interval and p-values. Prognostic performances of a penalized Cox model defined on the CycHyp signature were also compared with well-established prognosis models for breast cancer, namely Gene 70 (Mammaprint) (van′t Veer et al, Nature 415:530-536, 2002), Gene 76 (Wang et al, Lancet 365:671-679, 2005) and Oncotype DX (Paik et al, N Engl J Med 351:2817-2826, 2004) signatures. Those existing signatures were associated to specific prognostic models implemented in the genefu R package (Haibe-Kains et al, Genome Biol 11:R18, 2010).

Results Identification of the CycHyp Signature

Tumor cells were submitted to cycling hypoxia for 24 hours or maintained under normoxic conditions for the same period of time. Corresponding mRNA samples were analysed by hybridization using Human Gene 1.0 ST Affymetrix microarrays. Gene expression profiles of each cell type under normoxia vs. cycling hypoxia were produced to identify the most differentially expressed probesets.

The CycHyp signature was determined as the top 100 probesets with the lowest average pvalues over 200 resamplings, corresponding to 96 markers. These probesets are shown in the Table 11 below.

TABLE 11 GenBank Name of the Probeset Accession Number marker 1 8018860 NM_001168 BIRC5 2 8064156 NM_032527 ZGPAT 3 8138912 NM_012322 LSM5 4 7921786 NM_012394 PFDN2 5 8165011 NM_002003 FCN1 6 7964262 NM_001113201 NACA 7 7949792 NM_005608 PTPRCAP 8 8034101 NM_006858 TMED1 9 8168087 NM_001551 IGBP1 10 7963575 NM_001417 EIF4B 11 8124397 NM_005319 HIST1H1C 12 7975989 NM_031210 SLIRP 13 8127692 NM_000863 HTR1B 14 8127087 NM_000847 GSTA3 15 7941122 NM_013299 SAC3D1 16 7998692 NM_002528 NTHL1 17 8073623 NM_001044370 MPPED1 18 8014865 NM_006160 NEUROD2 19 8005726 NM_021012 KCNJ12 20 7966631 NM_022363 LHX5 21 8037853 NM_017854 TMEM160 22 8104136 NM_018942 HMX1 23 7948606 NM_014206 C11orf10 24 8044773 NM_006770 MARCO 25 7947015 NM_006292 TSG101 26 7931553 NM_003577 UTF1 27 7956876 NM_032338 LLPH 28 8117372 NM_003512 HIST1H2AC 29 8001329 NM_004352 CBLN1 30 8027205 NM_015965 NDUFA13 31 8042896 NM_016170 TLX2 32 7911532 NM_017900 AURKAIP1 33 8039923 NM_017900 AURKAIP1 34 7992043 BC001181 FAM173A 35 8063074 NM_080603 ZSWIM1 36 7992191 NM_012217 TPSD1 37 8108435 NM_181838 UBE2D2 38 8165309 NM_003792 EDF1 39 7946267 NM_022061 MRPL17 40 7945536 NM_016564 CEND1 41 8159609 NM_003731 SSNA1 42 8005471 NM_001031 RPS28 43 8025395 NM_001031 RPS28 44 7942824 NM_001031 RPS28 45 8170753 NM_014370 SRPK3 46 8032718 NM_001348 DAPK3 47 7967067 NM_001037495 DYNLL1 48 8159654 NM_015456 COBRA1 49 8011212 NM_003001 SDHC 50 8011968 NM_016060 MED31 51 7977440 NR_026800 KIAA0125 52 8016508 NM_007241 SNF8 53 8168567 NM_000307 POU3F4 54 8086317 NM_031899 GORASP1 55 8052834 BC005079 C2orf42 56 8073334 NM_014248 RBX1 57 7915846 NM_003684 MKNK1 58 8071920 NM_004175 SNRPD3 59 8032371 NM_031213 FAM108A1 60 7924884 NM_003493 HIST3H3 61 8006845 NM_000981 RPL19 62 7946812 NM_001017 RPS13 63 7949015 NM_001144936 C11orf95 64 8009784 NM_015971 MRPS7 65 8174509 NM_005274 GNG5 66 7906235 NM_005973 PRCC 67 8020179 NM_020412 CHMP1B 68 7947450 NM_005574 LMO2 69 8064370 NM_004609 TCF15 70 7955896 NM_016057 COPZ1 71 8137805 NM_003550 MAD1L1 72 8117334 NM_003538 HIST1H4A 73 8117368 NM_003542 HIST1H4C 74 7977507 NR_002312 RPPH1 75 7949410 BC018448 MALAT1 76 8150433 NM_152568 NKX6-3 77 8071168 NR_024583 POM121L8P 78 7989611 NM_032231 FAM96A 79 7980859 NM_001080113 80 8032782 NM_144615 TMIGD2 81 8110861 NM_032479 MRPL36 82 7901687 NM_182532 TMEM61 83 7916130 NM_138417 KTI12 84 8048712 BC033986 LOC440934 85 8018993 NM_001082575 RBFOX3 86 8032601 NM_032753 RAX2 87 8010719 NM_144999 LRRC45 88 8036584 NM_002307 LGALS7 89 8133209 NR_003666 SPDYE7P 90 8159501 NM_178536 LCN12 91 8028546 NM_002307 LGALS7 92 8065013 ENST00000427835 93 8018502 NM_173547 TRIM65 94 7903294 NM_033055 HIAT1 95 7989473 NM_001007595 C2CD4B 96 8054449 AK095987 FLJ38668 97 8081867 NM_016589 TIMMDC1 98 7934544 NM_144589 COMTD1 99 7968260 NM_145657 GSX1 100 8022952 NM_020180 CELF4

The heatmap (FIG. 1) made with the 100 probe sets of the CycHyp signature confirmed its excellent potential of discrimination between cycling hypoxia and normoxia.

The CycHyp Signature Predicts Clinical Outcome in Breast Cancer Patients

To evaluate the prognostic value of the CycHyp signature, we focused on breast cancer because of the very large amounts of well-annotated clinical data sets available and a clearly identified need to discriminate between patients at low and high risks among subgroups determined on the basis of clinicopathologic criteria (Reis-Filho et al, Lancet 378:1812-1823, 2011; Prat et al, Nat Rev Clin Oncol 9:48-57, 2011). Publicly available GEO data sets allowed us to collect information on the survival of 2,150 patients with primary breast cancer (see clinical features in Table 12).

TABLE 12 Breast Cancer Patient Demographics and Characteristics ER+/HER2− ER+/HER2− Node neg. All patients ER+/HER2− Node neg. Untreated n = 2150 n = 1452 n = 899 n = 590 No % No % No % No % Age ≦50 649 30 388 27 218 24 190 32  >50 945 44 649 45 367 41 237 40 NA 556 26 415 28 314 35 163 28 Tumor size ≦2 cm 742 35 537 37 474 53 424 72  >2 cm 473 22 326 22 210 23 158 28 NA 935 43 589 41 215 24 8 1 Grade 0-1 224 10 200 14 148 17 104 18 2 605 28 485 33 346 38 270 46 3 487 23 206 14 162 18 137 23 NA 834 39 561 39 243 27 79 13 Node status Negative 1329 62 899 62 899 100 590 100 Positive 821 38 553 38 0 0 0 0 Estrogen receptor Negative 443 21 0 0 0 0 0 0 Positive 1607 75 1452 100 899 100 590 100 NA 100 4 0 0 0 0 0 0 HER2 status Negative 1835 85 1452 100 899 100 590 100 Positive 315 15 0 0 0 0 0 0 Treatment None 901 42 590 41 590 66 590 100 Chemo- 691 32 410 28 73 8 0 0 therapy Hormono- 558 26 452 31 236 26 0 0 therapy

In order to exploit these data sets, we first transferred the Gene 1.0ST technology in the HGU133 platform. The 100 HGU1.0 ST probesets forming the CycHyp signature correspond to 94 unique Entrez GeneID in the NCBI database (Table 11), out of which 69 genes were available on the HGU133a platform. Those 69 genes are represented by 87 HGU133a probesets. The few datasets collected on HGU133plus2 were reduced to the probesets also present on HGU133a.

We then used the VDX dataset (GSE2034 and GSE5327) as a reference because of its large number of node negative untreated patients (Wang et al, Lancet 365:671-679, 2005). This training dataset was used to estimate a prognostic Cox proportional hazard model built on the CycHyp signature. The other datasets were used according to the methodology described by Haibe-Kains and colleagues (Haibe-Kains et al, Bioinformatics 24:2200-2208, 2008), to assess the prognostic performance of the CycHyp signature on independent samples. We first chose to evaluate our signature independently of the receptor status of the tumors. The prognostic potential of the CycHyp signature to discriminate between patients at low or high risk was confirmed with a HR=1.97 and a p-value=1.8. 10⁻¹² (FIG. 2A). We then focused on the ER+HER2− population which is known to be heterogeneous and thus difficult to treat (Reis-Filho et al, Lancet 378:1812-1823, 2011; Prat et al, Nat Rev Clin Oncol 9:48-57, 2011). The discriminating capacity of the CycHyp signature remained strikingly high in the ER+HER2− patient populations (HR=2.34, p-value=9. 10⁻¹², FIG. 2B). Finally, among this subpopulation of patients, we considered those with a node negative status (FIG. 2C) and among the latter, those who did not receive any treatment (FIG. 2D). Hazard ratios rose to 3.32 and 5.51 in these conditions (p-values=5.61. 10⁻¹⁰ and 8.15. 10⁻¹¹, respectively), further supporting the discriminating potential of the CycHyp signature. In particular, the data presented in FIG. 2D allowed to exclude any confounding influence of the potential benefit arising from the treatment administered to these patients and thus clearly identified a population of patients who remained inadequately untreated.

The CycHyp Signature Provides Significant Additional Prognostic Information to Available Multigene Assays

To evaluate the performance of the CycHyp signature, we compared it with other well-established prognostic multigene assays for breast cancer, namely Gene70 or Mammaprint (van't Veer et al, Nature 415:530-536, 2002), Gene76 (Wang et al, Lancet 365:671-679, 2005) and Oncotype Dx (Paik et al, N Engl J Med 351:2817-2826, 2004). Using the same set of ER+/HER2− node negative patients as used in FIG. 2D, we could determine the low vs. high risk patient stratification according to these signatures. The Balanced Classification Rate (BCR) represents the average between sensitivity and specificity to discriminate between patients with progressing disease vs. disease-free at 5 years. The BCR was significantly higher for the CycHyp signature than the three other multigene assays (FIG. 3A) (p-values=1.3e-4, 1.4e-21 and 6e-10 vs. Gene70, Gene76 and Oncotype DX, respectively). The sensitivity and the specificity of CycHyp were actually both above 70% while for each of the three other signatures, the specificity parameter was below 45% (FIG. 3A). The concordance index, which is the probability of a high risk patient to relapse before a low risk patient, was also higher with the CycHyp signature (FIG. 3A). The superior prognostic potential of the CycHyp signature could also be captured from the comparison of the Kaplan Meier curves obtained with the Gene 70, Gene76 and Oncotype DX signatures (HR in the 2-3 range) and that derived from the CycHyp signature (compare FIG. 3B with FIG. 2D).

The CycHyp Signature in Association with NPI Offers a Powerful Prognostic Tool

We then aimed to determine whether the CycHyp signature could improve the Nottingham Prognostic Index (NPI) for better predicting the survival of operable breast cancers.

The NPI algorithm combines nodal status, tumour size and histological grade and allows modeling a continuum of clinical aggressiveness with 3 subsets of patients divided into good, moderate, and poor prognostic groups with 15-year survival (Rakha et al, Breas Cancer Res 12:207, 2010; Galea et al, Breast Cancer Res Treat 22:207-219, 1992; Balslev et al, Breast Cancer Res Treat 32:281-290, 1994). Since few patients were assigned a poor index, we merged here the moderate and poor indices into a high risk group to facilitate the comparison with the CycHyp signature. We found that by integrating the CycHyp signature, an important proportion of patients could be reclassified to another risk group (FIG. 4). 52.9% of patients classified at high risk using the NPI algorithm were “false positive” since identified at low risk when using the CycHyp signature and actually exhibited a profile of survival closer to the low risk NPI patient (FIG. 4A). Inversely, using the CycHyp signature, we also identified in the patients at low risk based on the NPI criteria, 23.4% of patients with a risk profile closer to the patients with a negative outcome (FIG. 4B).

This increased discriminating potential remained highly relevant when considering all patients (FIG. 5A) or patients with a ER+HER2− status (FIG. 5B). Three subgroups of patients could be clearly identified: patients identified at low and high risks with both the CycHyp signature or the NPI criteria (Low-Low or High-High), and patients at intermediary risk, i.e. at low risk with NPI but high risk according to CycHyp signature (Low-High or false negative) or inversely (High-Low or false positive) (FIGS. 5A and 5B). Among the ER+HER2− patients with a node negative status (FIG. 5C), although a similar profiling of three subpopulations of patients could be proposed up to 5 years based on the combination of CycHyp signature and NPI, the gene signature was more efficient to predict survival on the longer term. Two subgroups of patients with either poor or good outcomes could actually be discriminated on the basis of the CycHyp signature (see L-L/H-L vs. L-H/H-H curves in FIG. 5C). Finally, when only considering untreated patients within the ER+HER2− node negative patients (FIG. 5D), four subgroups of patients were observed. Interestingly, within the subgroups of patients classified at intermediary risk, those at low risk based on the NPI but at high risk following the CycHyp (see L-H curve in FIG. 5D) had actually a worse outcome than those classified at high risk based on the NPI but at low risk according to the CycHyp signature (see red curve in FIG. 5D).

Numerical values obtained for patients and used for drafting FIGS. 5A-D are shown in the Table 13 below, wherein indicated p-values were derived from Mantel-Cox, log-rank tests.

TABLE 13 L-L H-L L-H HR p HR p HR p All H-L 2.33 3.73e−07 patients L-H 2.96 2.20e−04 1.22 0.392 H-H 3.86 1.49e−17 1.69 3.04e−07 1.39 0.135 ER+ HER2− H-L 2.72 3.45e−06 (N+/N−) L-H 3.35 5.67e−04 1.17 0.569 H-H 5.32 7.28e−17 1.97 3.63e−07 1.70 0.034 ER+ HER2− H-L 2.11 1.89e−02 (N−) L-H 4.41 9.83e−05 2.03 2.82e−02 H-H 5.61 4.38e−10 2.72 9.12e−06 1.37 0.265 ER+ HER2- H-L 3.93 5.42e−03 (N−) L-H 7.81 1.11e−04 1.88 1.43e−01 untreated H-H 14.34 9.17e−13 3.63 2.48e−05 1.98 0.044

Using the same protocol, the prognostic values of other signatures of the invention, comprising 10 probesets out of the 87 HGU133a probesets (themselves covering 69 genes of the CycHyp signature that are available on the HGU133a platform), were assessed.

The first 10-probesets signature comprises the following markers:

TABLE 14 Probeset Probeset GenBank Name of the (HGU 1.0 ST) (HGU133a) Accession Number marker 1 8018860 202095_s_at NM_001168 BIRC5 2 8064156 221848_at NM_032527 ZGPAT 3 8138912 202903_at NM_012322 LSM5 4 7921786 218336_at NM_012394 PFDN2 5 8165011 205237_at NM_002003 FCN1 6 7964262 200735_x_at NM_001113201 NACA 7 7949792 204960_at NM_005608 PTPRCAP 8 8034101 203679_at NM_006858 TMED1 9 8168087 202105_at NM_001551 IGBP1 10 7963575 211938_at NM_001417 EIF4B

Probesets according to the HGU 1.0 ST platform and to the HGU133a platform are indicated.

The prognostic efficiency of this signature is illustrated by the results of FIG. 6.

The second 10-probesets signature comprises the following markers:

TABLE 15 Probeset GenBank Name of the (HGU133a) Accession Number marker 1 202094_at AA648913 BIRC5 2 210334_x_at AB028869 BIRC5 3 204249_s_at NM_005574 LMO2 4 209731_at U79718 NTHL1 5 200018_at NM_001017 RPS13 6 218391_at NM_007241 SNF8 7 202904_s_at NM_012322 LSM5 8 208635_x_at BF976260 NACA 9 211747_s_at BC005938 LSM5 10 208904_s_at BC000354 RPS28

The prognostic efficiency of this signature is illustrated by the results of FIG. 7.

The third 10-probesets signature comprises the following markers:

TABLE 16 Probeset GenBank Name of the (HGU133a) Accession Number marker 1 202095_s_at NM_001168 BIRC5 2 221434_s_at NM_031210 C14orf156 3 202904_s_at NM_012322 LSM5 4 33 211747_s_at BC005938 LSM5 5 200703_at NM_003746 DYNLL1 6 218391_at NM_007241 SNF8 7 208903_at BF431363 RPS28 8 200018_at NM_001017 RPS13 9 208635_x_at BF976260 NACA 10 218177_at AA293502 CHMP1B

The prognostic efficiency of this signature is illustrated by the results of FIG. 8.

The fourth 10-probesets signature comprises the following markers:

TABLE 17 Probeset GenBank Name of the (HGU133a) Accession Number marker 1 202095_s_at NM_001168 BIRC5 2 211938_at BF247371 EIF4B 3 221434_s_at NM_031210 C14orf156 4 202904_s_at NM_012322 LSM5 5 33 211747_s_at BC005938 LSM5 6 200703_at NM_003746 DYNLL1 7 218391_at NM_007241 SNF8 8 208903_at BF431363 RPS28 9 200018_at NM_001017 RPS13 10 208635_x_at BF976260 NACA

The prognostic efficiency of this signature is illustrated by the results of FIG. 9.

Taken together, these data demonstrate that the signatures of the present invention, which are derived from the transcriptomic adaptation of tumor cells to cycling hypoxia is prognostic of cancer.

To confirm the specificity of these results, random gene signatures were tested for their prognostic capacity (negative control). These random signatures were constituted of 10 genes randomly selected amongst the totality of the genome. To have a significant value, 1000 such random signatures were used according the same methodology than with the CycHyp signature. The logrank test (or Mantel-Haenszel test; Balsev et al, Breast Cancer Res Treat, 1994) is commonly used to assess whether there is a significant survival difference between risk groups. The discrimination between risk groups was significantly higher (P<0.001) with the CycHyp signature as compared to each of the random signatures, therefore validating the prognostic potential of the CycHyp signature (right panel, FIG. 10).

Example 2 Alternative Lists of 10 Genes Methods

To assess the prognosis value of an alternative list of 10 genes representative of Cycling Hypoxia, we compared the CycHyp signature with alternative lists of 10 probesets (Table 18) out of the 87 HGU133a probesets (themselves covering 69 genes of the CycHyp signature that are available on the HGU133a platform but without overlap with the CycHyp signature of 10 genes shown in Table 8. Using the same set of ER+/HER2-node negative patients as used in FIG. 2D, we could determine the low vs. high risk patient stratification according to these signatures.

TABLE 18 Probeset GenBank Name of the (HGU133a) Accession number marker 1 204249_s_at NM_005574 LMO2 2 209731_at U79718 NTHL1 3 200018_at NM_001017 RPS13 4 218391_at NM_007241 SNF8 5 208904_s_at BC000354 RPS28 6 222216_s_at AK026857 MRPL17 7 201758_at NM_006292 TSG101 8 200703_at NM_003746 DYNLL1 9 209467_s_at BC002755 MKNK1 10 208903_at BF431363 RPS28

Results

The prognostic efficiency of one of these alternative signatures is illustrated by the results of FIG. 11. Such a model may have a good prognosis performance with a hazard ratio of 2.78 for that particular alternative list, but is significantly lesser than the CycHyp model (HR=5.51, see FIG. 2D).

Another 10-probesets signature wherein one probeset of Table 18 is replaced by one probeset of Table 14 comprises the following markers:

TABLE 19 Probeset GenBank Name of the (HGU133a) Accession number marker 1 211938_at BF247371 EIF4B 2 204249_s_at NM_005574 LMO2 3 209731_at U79718 NTHL1 4 200018_at NM_001017 RPS13 5 218391_at NM_007241 SNF8 6 208904_s_at BC000354 RPS28 7 222216_s_at AK026857 MRPL17 8 201758_at NM_006292 TSG101 9 200703_at NM_003746 DYNLL1 10 209467_s_at BC002755 MKNK1

The prognostic efficiency of this signature is illustrated by the results of FIG. 12.

Another 10-probesets signature where two probesets of Table 18 are replaced by two probesets of Table 14 comprises the following markers:

TABLE 20 Probeset GenBank Name of the (HGU133a) Accession number marker 1 202095_s_at NM_001168 BIRC5 2 211938_at BF247371 EIF4B 3 204249_s_at NM_005574 LMO2 4 209731_at U79718 NTHL1 5 200018_at NM_001017 RPS13 6 218391_at NM_007241 SNF8 7 208904_s_at BC000354 RPS28 8 222216_s_at AK026857 MRPL17 9 201758_at NM_006292 TSG101 10 200703_at NM_003746 DYNLL1

The prognostic efficiency of this signature is illustrated by the results of FIG. 13.

Equivalent results were obtained with the other alternative lists tested. These results thus demonstrated that any combination of 10 genes of Table 5 or Table 11 has a high prognosis performance.

Example 3 Comparison of the Signature of Cyclic Hypoxia of the Invention (CycHyp) with a Signature of Continuous Hypoxia (ContHyp) Methods

Using the same protocol as for the identification of the CycHyp signature, we determined a ContHyp signature which corresponds to continuous hypoxia conditions, i.e. 24 h continuous exposure to 1% O₂.

Results

A heatmap made with the 100 probe sets of the CycHyp signature shown its important potential of discrimination between cycling hypoxia and continuous hypoxia (data not shown).

We then used the Gene Set Enrichment Analysis described by Subramanian et al. (Proc Natl Acad Sci USA, 2005) which is a method for identifying differentially expressed genes that share some characteristic. The analysis indicated that when considering differentially expressed probesets (after FDR correction), only 2 gene sets were significantly enriched in the CycHyp signature whereas 52 gene sets were enriched in the ContHyp signature, including 17 directly related to hypoxia.

Also, when using the MSigDB molecular signature database referring to hypoxia or HIF (www.broadinstitute.org), we found only 13 hypoxia gene sets sharing, on average, 1.4 gene with CycHyp whereas 44 hypoxia gene sets showed overlap with ContHyp with an average of 6.6 common genes.

To further validate the prognosis significance of the CycHyp signature compared to the ContHyp signature, we performed a comparison with random gene signatures according to the methodology described by Venet et al. (PLoS Comput Biol, 2011) and Beck et al. (PLoS Comput Biol, 2013). FIG. 10 shows the distribution of the p-values (log rank test in log 10) for 1000 randomly generated signatures together with the p-values of the CycHyp and ContHyp signatures. The discrimination between risk groups was significantly higher (P<0.001) with the CycHyp signature as compared to each of the random signatures whereas the ContHyp signature (left panel) was not significantly better (vs. random ones; P=0.141).

Using the same methodology, we examined the prognostic capacity of the ContHyp signature (discriminating between normoxia and continuous hypoxia). The performance of the ContHyp signature was satisfactory on the ER+HER2− untreated population (HR=2.58, p-value=1.46e-4, see FIG. 14) but was significantly lower (p-value=3.61e-8) than the CycHyp signature.

Taken together, these data confirm the significantly high value of the CycHyp signature of the present invention, and confirm the prognostic advantage of a signature based on cyclic hypoxia compared to a signature based on continuous hypoxia.

Example 4 CycHyp Signature on Colorectal Cancer Patients Patients and Methods

To validate the use of the CycHyp signature on colorectal cancer, we used 2 public microarray data sets: GSE39582 (566 patients) and GSE17536 (177 patients).

The GSE39582 dataset was used as the training set used to estimate a prognostic model of the clinical outcome. This training dataset was used to estimate a prognostic Cox or equal weights linear (EWL) regression models built on the CycHyp signature. The GSE17536 dataset was then used according to the methodology described for breast cancer samples to assess the prognostic performance of the CycHyp signature on independent samples.

Results

As for breast cancer, we first compared the CycHyp signature with randomly selected genes on the colon data sets. Each random signature has the same size as the CycHyp signature. We generated 1,000 such random signatures and use the same methodology to estimate a prognosis model from the GSE39582 dataset. We then assess the performance of those prognosis models on the independent validation sets of 177 patients (GSE17536).

FIG. 15 represents in gray the distribution of those prognosis models built from random signatures on the stage 2 patients. The discrimination between high and low risk groups is assessed according to a logrank test and its associated p-value (reported in log 10 scale). The logrank p-values of the CycHyp signature is represented with black dots on the same plot. The CycHyp signature is significantly better than random signature on the stage 2 patients (p-value 0:027).

To evaluate the discriminating capacity of the CycHyp signature, we chose to focus on the stage II colorectal cancer population which is known to be heterogeneous and thus difficult to treat. The prognostic efficiency of the CycHyp signature is illustrated by the results of FIG. 16. The discriminating capacity of the CycHyp signature was strikingly high in this patient population (HR=5.35, p-value=0.03) when compared with the whole colorectal cancer patient population (HR=2.52, p-value=0.017) (not shown).

These results demonstrate that the CycHyp signature of the invention also has high prognosis performance for colorectal cancer.

Example 5 Prognostic Performance of a Signature Consisting of BIRC5, IGBP1 and EIF4B Methods

The prognostic values of another signature of the invention, comprising 3 probesets, was assessed. Using the same set of ER+/HER2− node negative patients as used in FIG. 2D, we could determine the low vs. high risk patient stratification according to these signatures.

The 3-probesets signature comprises the following markers:

TABLE 21 Probeset GenBank Name of the (HGU133a) Accession number marker 1 202095_s_at NM_001168 BIRC5 2 202105_at NM_001551 IGBP1 3 211938_at BF247371 EIF4B

Results

The prognostic efficiency of this signature is illustrated by the results of FIG. 17. Such a model has a good prognosis performance with a hazard ratio of 5.09 that is almost as good as the CycHyp model (HR=5.51, see FIG. 2D). 

1. A non-invasive method for the prognosis of cancer in a subject, or for predicting the response of a subject to a specific treatment, wherein said method comprises obtaining a sample from the subject, and assessing the expression of markers of a signature comprising at least 2 cycling hypoxia markers.
 2. The non-invasive method according to claim 1, wherein said signature comprises at least 3 cycling hypoxia markers.
 3. The non-invasive method according to claim 1, wherein said cycling hypoxia markers are selected from the list of 1379 cycling hypoxia markers of Table 1, fragments, variants and equivalents thereof.
 4. The non-invasive method according to claim 1, wherein said cycling hypoxia markers are selected from the list of 651 cycling hypoxia markers of Table 2, fragments, variants and equivalents thereof.
 5. The non-invasive method according to claim 1, wherein said cycling hypoxia markers are selected from the list of 298 cycling hypoxia markers of Table 3, fragments, variants and equivalents thereof.
 6. The non-invasive method according to claim 1, wherein said cycling hypoxia markers are selected from the list of 167 cycling hypoxia markers of Table 4, fragments, variants and equivalents thereof.
 7. The non-invasive method according to claim 1, wherein said cycling hypoxia markers are selected from the list of 96 cycling hypoxia markers of Table 5, fragments, variants and equivalents thereof.
 8. The non-invasive method according to claim 1, wherein said cycling hypoxia markers are selected from the list of 74 cycling hypoxia markers of Table 6, fragments, variants and equivalents thereof.
 9. The non-invasive method according to claim 1, wherein said cycling hypoxia markers are selected from the list of 37 cycling hypoxia markers of Table 7, fragments, variants and equivalents thereof.
 10. The non-invasive method according to claim 1, wherein said cycling hypoxia markers are selected from the list of 10 cycling hypoxia markers of Table 8, fragments, variants and equivalents thereof.
 11. The non-invasive method according to claim 1, wherein said signature comprises the 10 cycling hypoxia markers of Table 8, variants, fragments and equivalents thereof.
 12. The non-invasive method according to claim 1, wherein said method comprises mathematically combining the expression profile of markers in a score.
 13. The non-invasive method according to claim 1, wherein said sample is a biopsy sample or a bodily fluid sample of said subject.
 14. The non-invasive method according to claim 1, further comprising comparing said expression with a reference expression profile.
 15. A kit for implementing the non-invasive method according to claim 1, wherein said kit comprises means for determining the expression of the cycling hypoxia markers of the signature.
 16. The kit according to claim 15, wherein said means for determining the expression of the markers of the signature is a microarray comprising probes specific for said cycling hypoxia markers.
 17. The kit according to claim 15, wherein said means for determining the expression of the cycling hypoxia markers are qPCR primers specific for said cycling hypoxia markers.
 18. The kit according to claim 15, wherein said means for determining the expression of the cycling hypoxia markers are probes to detect qPCR amplicons obtained with qPCR primers. 